Spiro compounds and pharmaceutical use thereof

ABSTRACT

The Spiro compound represented by the following general formula [Ia], its pharmaceutically acceptable salt or a solvate thereof

TECHNICAL FIELD

The present invention relates to spiro compounds having GPR40 agonistactivity, a pharmaceutically acceptable salt thereof or a solvatethereof, a pharmaceutical composition containing the same and apharmaceutical use thereof.

BACKGROUND ART

Diabetes mellitus (DM) is a disease characterized by sugar and lipidmetabolic disorder, and there is a risk that it may lead to variouspathognomonic complexities resulting from an abnormally high blood sugarlevel (blood glucose level). The number of patients with diabetesmellitus in the world is estimated to exceed 180 million as of 2006.

The onset of diabetes mellitus has been reported to relate toenvironmental factors such as overeating, obesity, lack of exercise inaddition to genetic factors. Diabetes mellitus is mainly classified intotype 1 diabetes mellitus (insulin-dependent diabetes mellitus (IDDM))and type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus(NIDDM)). Most of the patients (about 90%) suffer from type 2 diabetesmellitus.

Type 1 diabetes mellitus is characterized by loss of insulin-secreting βcells of the islets of Langerhans in the pancreas and type 2 diabetesmellitus is caused by two factors which are deficient insulin secretiondue to reduced glucose sensitivity of pancreatic β cells and reducedinsulin sensitivity of peripheral tissues such as muscle, adipose andliver.

Currently, exercise therapy and diet therapy are used in the treatmentand prevention of diabetes mellitus, and medication therapy is used aswell.

A typical medication therapy in current use includes insulin therapy andoral hypoglycemic agents. The oral hypoglycemic agents (OHAs) includesulfonylureas (SUs), biguanides, α-glucosidase inhibitors (α GIs) andthiazolidine derivatives (TZDs).

However, these medicines have side effects such as hypoglycemia, liverdamage and gastrointestinal disease, and therefore an effective methodfor using these medicines has been studied and developed. In addition,the research on a novel mechanism-based treatment and prevention methodhas been underway actively.

Recent studies of G protein-coupled receptors (GPCRs) have led to thediscovery of GPR40 (G protein-coupled receptor 40), also known as freefatty acid receptor 1 (FFR1), which is a protein having seventransmembrane domains and whose ligand is a free fatty acid, inparticular a mid- and long-chain fatty acid. GPR40 is known to highlyexpress in the pancreas of rodents, in particular in pancreatic β cells.Meanwhile, GPR40 is shown to express in the brain as well as pancreaticβ cells of human.

With regard to the function of GPR40, it is known that a free fattyacid, a ligand for GPR40, acts on GPR40 in pancreatic β cells, andthereby β cells secrete insulin depending on glucose level. In addition,analysis of GPR40 knockout mice reveals that GPR40 may be involved inpathology of obesity and diabetes mellitus.

As a GPR40-related disease, diabetes mellitus, hyperglycemia, impairedglucose tolerance, insulin resistance, impaired fasting glucose,diabetic neuropathy, diabetic nephropathy, diabetic retinopathy,ketoacidosis, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, dyslipemia, hyperlipoproteinemia, metabolicsyndrome, obesity, atherosclerosis, etc. are known. For these reasons,attention has been drawn to GPR40 as a novel target of diabetesmellitus.

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

The object of the present invention is to provide a medicament formodulating the function of GPR40, in particular, a medicament as GPR40agonist for treating or preventing diabetes mellitus, hyperglycemia,impaired glucose tolerance, impaired fasting glucose and the like.

Means for Solving the Problem

The present inventors have intensively carried out investigations todevelop a medicament as GPR40 agonist for treating or preventingdiabetes mellitus, hyperglycemia, impaired glucose tolerance, impairedfasting glucose and the like, and found a spiro compound having GPR40agonist activity. Based on the findings, the present inventors havecarried out further investigations and completed the present invention.

Namely, the present invention relates to the followings.

1) A Spiro compound of the following general formula [Ia]:

(wherein R¹ is(1) a hydrogen atom,(2) a C₁-C₆ alkyl group,(3) a C₂-C₆ alkenyl group,(4) a C₂-C₆ alkynyl group,(5) a C₁-C₆ alkoxy group,(6) a hydroxy C₁-C₆ alkyl group,(7) a C₁-C₆ alkoxy (C₁-C₆) alkyl group,(8) —CONR¹¹R¹² in which R¹¹ and R¹² are the same or different and eachrepresents a hydrogen atom or a C₁-C₆ alkyl group,(9) a phenyl group or(10) a five-membered heteroaryl group which has at least one heteroatomselected from the group consisting of a nitrogen atom, an oxygen atomand a sulfur atom, and which may be substituted by a C₁-C₆ alkyl group;

R² is

(1) a halogen atom,(2) a C₁-C₆ alkyl group,(3) a hydroxy group or(4) a C₁-C₆ alkoxy group;p is 0, 1, 2 or 3;X is a carbon atom or a nitrogen atom;m1 is 0, 1 or 2;m2 is 0 or 1;a spiro-ring AB may be substituted by 1 to 5 same or differentsubstituent(s) selected from the group consisting of(1) a hydroxy group,(2) a C₁-C₆ alkyl group,(3) a C₁-C₆ alkoxy group and(4) an oxo group;n1 is 0, 1, 2, 3 or 4;n2 is 1, 2, 3 or 4;n3 is 0, 1 or 2 with the proviso that n2+n3 is 2, 3 or 4; anda bond represented by the symbol:

means a single bond or a double bond with proviso that three contiguouscarbon atoms do not constitute an allene bond represented by theformula:

C═C═C

),a pharmaceutically acceptable salt thereof or a solvate thereof.

2) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 1), wherein the spiro-ring ABis represented by the formula:

(wherein each symbol is as defined above).

3) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 1) or 2, wherein the numberof the double bond in ring A of the spiro-ring AB is 0 or 1.

4) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to any one of the above 1) to 3), whereinthe number of the double bond in ring B of the spiro-ring AB is 0 or 1.

5) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to any one of the above 1) to 4), whereinn3 is 1 or 2.

6) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to any one of the above 1) to 5), whereinthe spiro-ring AB may be substituted by 1 to 3 same or differentsubstituent(s).

7) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to any one of the above 1) to 6),

wherein R¹ is(1) a hydrogen atom,(2) a C₁-C₆ alkyl group,(3) a C₂-C₆ alkenyl group,(4) a C₂-C₆ alkynyl group,(5) a C₁-C₆ alkoxy group,(6) a C₁-C₆ alkoxy (C₁-C₆) alkyl group,(7) —CONR¹¹R¹² in which R¹¹ and R¹² are the same or different and eachrepresents a hydrogen atom or a C₁-C₆ alkyl group, or(8) a five-membered heteroaryl group which has at least one heteroatomselected from the group consisting of a nitrogen atom, an oxygen atomand a sulfur atom, and which may be substituted by a C₁-C₆ alkyl group.

8) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to any one of the above 1) to 7),

wherein R¹ is(1) a hydrogen atom,(2) a C₂-C₆ alkenyl group,(3) a C₂-C₆ alkynyl group,(4) a C₁-C₆ alkoxy group or(5) a five-membered heteroaryl group which has at least one heteroatomselected from the group consisting of a nitrogen atom, an oxygen atomand a sulfur atom, and which may be substituted by a C₁-C₆ alkyl group.

9) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to any one of the above 1) to 8), whereinp is 0 or 1.

10) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to any one of the above 1) to 9),

wherein R² is(1) a C₁-C₆ alkyl group,(2) a hydroxy group or(3) a C₁-C₆ alkoxy group.

11) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to any one of the above 1) to 10), whereinm1 is 0 or 1.

12) A pharmaceutical composition, which comprises the spiro compound,the pharmaceutically acceptable salt thereof or the solvate thereofaccording to any one of the above 1) to 11), and a pharmaceuticallyacceptable carrier.

13) A GPR40 agonist medicament, which comprises the spiro compound, thepharmaceutically acceptable salt thereof or the solvate thereofaccording to any one of the above 1) to 11), as an effective ingredient.

14) An insulin secretion-promoting agent or a hypoglycemic agent, whichcomprises the spiro compound, the pharmaceutically acceptable saltthereof or the solvate thereof according to any one of the above 1) to11), as an effective ingredient.

15) A pharmaceutical composition for treating or preventing a diseaseselected from the group consisting of diabetes mellitus, hyperglycemia,impaired glucose tolerance and impaired fasting glucose, which comprisesthe spiro compound, the pharmaceutically acceptable salt thereof or thesolvate thereof according to any one of the above 1) to 11), as aneffective ingredient.

16) A use of the spiro compound, the pharmaceutically acceptable saltthereof or the solvate thereof according to any one of the above 1) to11), for the production of a GPR40 agonist medicament.

17) A use of the spiro compound, the pharmaceutically acceptable saltthereof or the solvate thereof according to any one of the above 1) to11), for the production of an insulin secretion-promoting agent or ahypoglycemic agent.

18) A use of the spiro compound, the pharmaceutically acceptable saltthereof or the solvate thereof according to any one of the above 1) to11), for the production of a pharmaceutical composition for treating orpreventing a disease selected from the group consisting of diabetesmellitus, hyperglycemia, impaired glucose tolerance and impaired fastingglucose.

19) A method for activating GPR40, which comprises administration of thespiro compound, the pharmaceutically acceptable salt thereof or thesolvate thereof according to any one of the above 1) to 11) to a mammalin a pharmaceutically effective amount.

20) A method for promoting insulin secretion or lowering blood glucoselevel, which comprises administration of the spiro compound, thepharmaceutically acceptable salt thereof or the solvate thereofaccording to any one of the above 1) to 11) to a mammal in apharmaceutically effective amount.

21) A method for treating or preventing a disease selected from thegroup consisting of diabetes mellitus, hyperglycemia, impaired glucosetolerance and impaired fasting glucose, which comprises administrationof the spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to any one of the above 1) to 11) to amammal in a pharmaceutically effective amount.

22) A spiro compound of the following general formula [I]:

(wherein R¹ is(1) a hydrogen atom,(2) a C₁-C₄ alkyl group,(3) a C₂-C₄ alkenyl group,(4) a C₂-C₄ alkynyl group,(5) a C₁-C₄ alkoxy group,(6) a hydroxy C₁-C₄ alkyl group,(7) a C₁-C₄ alkoxy (C₁-C₄) alkyl group,(8) —CONR¹¹R¹² in which R¹¹ and R¹² are the same or different and eachrepresents a hydrogen atom or a C₁-C₄ alkyl group,(9) a phenyl group or(10) a five-membered heteroaryl group which has at least one heteroatomselected from a nitrogen atom, an oxygen atom and a sulfur atom, andwhich may be substituted by a C₁-C₄ alkyl group;m1 is 0, 1 or 2;m2 is 0 or 1;a spiro-ring AB may be substituted by 1 to 5 same or differentsubstituent(s) selected from(1) a hydroxy group and(2) a C₁-C₄ alkyl group;n1 is 2, 3 or 4;n2 is 1, 2 or 3;n3 is 0, 1 or 2 with the proviso that n2+n3 is 2 or 3; anda bond represented by the symbol:

means a single bond or a double bond with proviso that three contiguouscarbon atoms do not constitute an allene bond represented by theformula:

C═C═C

),a pharmaceutically acceptable salt thereof or a solvate thereof.

23) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 22), wherein the spiro-ringAB is represented by the formula:

(wherein each symbol is as defined above).

24) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 22), wherein the number ofthe same or different substituent(s) of the spiro-ring AB is 1, 2 or 3.

25) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 22), wherein R¹ is

(1) a hydrogen atom,(2) a C₁-C₄ alkyl group,(3) a C₂-C₄ alkenyl group,(4) a C₂-C₄ alkynyl group,(5) a C₁-C₄ alkoxy group,(6) a C₁-C₄ alkoxy (C₁-C₄) alkyl group,(7) —CONR¹¹R¹² in which R¹¹ and R¹² are the same or different and eachrepresents a hydrogen atom or a C₁-C₄ alkyl group, or(8) a five-membered heteroaryl group which has at least one heteroatomselected from a nitrogen atom, an oxygen atom and a sulfur atom, andwhich may be substituted by a C₁-C₄ alkyl group.

26) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 23), wherein R¹ is

(1) a hydrogen atom,(2) a C₂-C₄ alkenyl group,(3) a C₂-C₄ alkynyl group,(4) a C₁-C₄ alkoxy group or(5) a five-membered heteroaryl group which has at least one heteroatomselected from a nitrogen atom, an oxygen atom and a sulfur atom, andwhich may be substituted by a C₁-C₄ alkyl group.

27) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 22), wherein m1 is 0 or 1.

28) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 22), wherein m2 is 0.

29) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 22), wherein n1 is 2 or 3.

30) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 22), wherein n2 is 1 or 2.

31) The spiro compound, the pharmaceutically acceptable salt thereof orthe solvate thereof according to the above 22), wherein n3 is 1 or 2.

32) A pharmaceutical composition, which comprises the spiro compound,the pharmaceutically acceptable salt thereof or the solvate thereofaccording to any one of the above 22) to 31), and a pharmaceuticallyacceptable carrier.

33) A GPR40 agonist medicament, which comprises the spiro compound, thepharmaceutically acceptable salt thereof or the solvate thereofaccording to any one of the above 22) to 31), as an effectiveingredient.

34) An insulin secretion-promoting agent or a hypoglycemic agent, whichcomprises the spiro compound, the pharmaceutically acceptable saltthereof or the solvate thereof according to any one of the above 22) to31), as an effective ingredient.

35) A pharmaceutical composition for treating or preventing a diseaseselected from the group consisting of diabetes mellitus, hyperglycemia,impaired glucose tolerance and impaired fasting glucose, which comprisesthe spiro compound, the pharmaceutically acceptable salt thereof or thesolvate thereof according to any one of the above 22) to 31), as aneffective ingredient.

36) A use of the spiro compound, the pharmaceutically acceptable saltthereof or the solvate thereof according to any one of the above 22) to31), for the production of a GPR40 agonist medicament.

37) A use of the spiro compound, the pharmaceutically acceptable saltthereof or the solvate thereof according to any one of the above 22) to31), for the production of an insulin secretion-promoting agent or ahypoglycemic agent.

38) A use of the spiro compound, the pharmaceutically acceptable saltthereof or the solvate thereof according to any one of the above 22) to31), for the production of a pharmaceutical composition for treating orpreventing a disease selected from the group consisting of diabetesmellitus, hyperglycemia, impaired glucose tolerance and impaired fastingglucose.

Effect of the Invention

The spiro compound, the pharmaceutically acceptable salt thereof and thesolvate thereof according to the present invention are useful as amedicament for modulating the function of GPR40, in particular, aninsulin secretion-promoting agent or a hypoglycemic agent to serve asGPR40 agonist. The spiro compound, the pharmaceutically acceptable saltthereof and the solvate thereof are also useful as a medicament fortreating or preventing diabetes mellitus, hyperglycemia, impairedglucose tolerance, impaired fasting glucose and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

The substituents as used herein are defined as follows.

“C₁-C₆ alkyl” refers to a linear or branched alkyl group having 1 to 6carbon atoms and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, tert-pentyl and hexyl. Preferred is a linear orbranched alkyl group having 1 to 4 carbon atoms. More preferred isethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl.

“C₂-C₆ alkenyl” refers to a linear or branched alkenyl group having 2 to6 carbon atoms, and includes, for example, vinyl, 1-propenyl,2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl,2-methyl-2-propenyl, n-pentenyl, isopentenyl, neopentenyl,1-methylpropenyl, n-hexenyl, isohexenyl, 1,1-dimethylbutenyl,2,2-dimethylbutenyl, 3,3-dimethylbutenyl, 3,3-dimethylpropenyl and2-ethylbutenyl. Preferred is a linear or branched alkenyl group having 2to 4 carbon atoms. More preferred is vinyl, 1-propenyl, 2-propenyl orisopropenyl.

“C₂-C₆ alkynyl” refers to a linear or branched alkynyl group having 2 to6 carbon atoms, and includes, for example, ethynyl,prop-2-yn-1-yl(propargyl), prop-1-yn-1-yl, 1-butyn-1-yl, 1-butyn-3-yl,1-butyn-4-yl, 2-butyn-1-yl, pentynyl and hexynyl. Preferred is a linearor branched alkynyl group having 2 to 4 carbon atoms. More preferred isethynyl, prop-2-yn-1-yl(propargyl) or prop-1-yn-1-yl.

“C₁-C₆ alkoxy” is a substituent represented by the formula: —O—(C₁-C₆alkyl), and includes, for example, methoxy, ethoxy, n-propoxy,isopropyloxy, n-butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy(tert-butoxy), pentyloxy, tert-pentyloxy and hexyloxy. Preferred is aC₁-C₄ alkoxy group, an alkoxy group represented by the formula:—O—(C₁-C₄ alkyl). More preferred is methoxy, ethoxy, n-propoxy orisopropyloxy.

“C₂-C₆ alkylene” refers to a linear alkylene group having 2 to 6 carbonatoms and it may be substituted by a C₁-C₆ alkyl, C₁-C₆ alkoxy, hydroxyor oxo group. Its examples include —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—(CH₂)₅—, and —(CH₂)₆—.

“Hydroxy C₁-C₆ alkyl” refers to the above-defined “C₁-C₆ alkyl” groupmono- or di-substituted by a hydroxy group, preferably mono-substitutedby a hydroxy group, and includes, for example, hydroxymethyl,2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl and 6-hydroxyhexyl.Preferred is hydroxy C₁-C₄ alkyl. More preferred is hydroxylmethyl.

“C₁-C₆ alkoxy (C₁-C₆) alkyl” refers to the above-defined “C₁-C₆ alkyl”group mono- or di-substituted by the above-defined “C₁-C₆ alkoxy” group,and includes, for example, methoxymethyl, ethoxymethyl, n-propoxymethyl,t-butoxymethyl, 2-methoxyethyl, 1-methoxy-1-methylethyl,1,2-dimethoxyethyl, 3-methoxypropyl, 3-ethoxypropyl, 2,3-diethoxypropyl,4-methoxybutyl, 5-methoxypentyl, 5-ethoxypentyl, 6-methoxyhexyl,6-ethoxyhexyl, pentyloxymethyl and hexyloxymethyl. Preferred is C₁-C₄alkoxy (C₁-C₄) alkyl. More preferred is mono-(C₁-C₄ alkoxy)-substituted(C₁-C₄) alkyl such as methoxymethyl, ethoxymethyl, n-propoxymethyl,t-butoxymethyl, 2-methoxyethyl, 1-methoxy-1-methylethyl,3-methoxypropyl, 3-ethoxypropyl and 4-methoxybutyl. Even more preferredis methoxymethyl.

The group represented by the formula: —CONR¹¹R¹² includes, for example,carbamoyl, methylaminocarbonyl, dimethylaminocarbonyl,ethylaminocarbonyl, diethylaminocarbonyl, methyl(ethyl)aminocarbonyl,n-propylaminocarbonyl, methyl(n-propyl)aminocarbonyl,n-butylaminocarbonyl, di-n-butylaminocarbonyl, n-pentylaminocarbonyl,di-n-pentylaminocarbonyl, methyl(n-pentyl)aminocarbonyl,hexylaminocarbonyl, di-hexylaminocarbonyl andmethyl(hexyl)aminocarbonyl. Preferred is methylaminocarbonyl ordimethylaminocarbonyl.

“A five-membered heteroaryl group having at least one heteroatomselected from a nitrogen atom, an oxygen atom and a sulfur atom”, whichis also called a five-membered heteroaryl group having at least oneheteroatom selected from the group consisting of a nitrogen atom, anoxygen atom and a sulfur atom, is preferably a five-membered heteroarylgroup having at least one nitrogen atom. More preferred is afive-membered heteroaryl group having 1 to 4 nitrogen atoms and, oneoxygen atom or/and one sulfur atom. Examples of the five-memberedheteroaryl group include pyrolyl, imidazolyl, triazolyl, tetrazolyl,furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl,isoxazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and1,3,4-thiadiazolyl. Preferred is tetrazolyl, oxazolyl or thiazolyl andmore preferred is tetrazolyl or oxazolyl. Especially preferred istetrazolyl.

A substituent for the five-membered heteroaryl group is preferably aC₁-C₆ alkyl group, more preferably a C₁-C₄ alkyl group. Even morepreferred is methyl, ethyl, n-propyl or isopropyl. Especially preferredis methyl.

“A halogen atom” refers to a fluorine atom, a chlorine atom, a bromineatom or an iodine atom, and is preferably a fluorine atom or a chlorineatom.

“A leaving group” refers to a chlorine atom, a bromine atom, an iodineatom, a methanesulfonyloxy group, a para-toluenesulfonyloxy group, abenzenesulfonyloxy group, an acetyl group or atrifluoromethanesulfonyloxy group, and is preferably a bromine atom oran iodine atom.

In the following explanation of the preparation method, a leaving groupof Lv₁ is preferably a chlorine atom, a bromine atom, amethanesulfonyloxy group, a para-toluenesulfonyloxy group, abenzenesulfonyloxy group or a trifluoromethanesulfonyloxy group, morepreferably a chlorine atom, a bromine atom or a methanesulfonyloxygroup.

A leaving group of Lv₂ is preferably a chlorine atom, a bromine atom, amethanesulfonyloxy group, a para-toluenesulfonyloxy group, abenzenesulfonyloxy group, an acetyl group or atrifluoromethanesulfonyloxy group, more preferably a methanesulfonyloxygroup, a trifluoromethanesulfonyloxy group or an acetyl group.

Preferably, L₁ and L₂ are each independently a chlorine atom, a bromineatom, a methanesulfonyloxy group, a para-toluenesulfonyloxy group, abenzenesulfonyloxy group, a dimethylsulfonium group or atrifluoromethanesulfonyloxy group. More preferably, L₁ and L₂ are eachindependently a bromine atom or a methanesulfonyloxy group.

“A hydroxy protecting group” as used herein refers to an ether-based oracetyl-based hydroxy protecting group. The ether-based hydroxyprotecting group refers to, for example, a tetrahydropyranyl group, abenzyl group, a paramethoxy benzyl group, a tert-butyldiphenylsilylgroup, a tert-butyldimethylsilyl group or a trimethylsilyl group, and ispreferably a tetrahydropyranyl group, a paramethoxy benzyl group, atert-butyldiphenylsilyl group or a tert-butyldimethylsilyl group. Theacetyl-based hydroxy protecting group is an acetyl group, a benzoylgroup or a para-nitrobenzoyl group, preferably an acetyl group.

“Spiro-ring AB” represented by the following partial structural formula:

(wherein each symbol is as defined above)refers to a monospiro hydrocarbon with two monocyclic rings, in which acarbon atom a of ring A represented by the following partial structuralformula:

is a spiro carbon atom identical with a carbon atom β of ring Brepresented by the following partial structural formula:

and both rings are spiro-condensed (spiro-bonded) at the spiro carbonatom. The following symbol bound to the ring B

refers to the following partial structural formula:

“Ring A of the spiro-ring AB” refers to a ring A part of theabove-mentioned spiro-ring AB, which is a 3- to 7-membered saturated orunsaturated hydrocarbon ring optionally having 1 to 3 double bonds,preferably one double bond in the ring. n1 is 0, 1, 2, 3 or 4,preferably 2 or 3.

Examples of the ring A of the spiro-ring AB″ are as follows:

Preferred is ring A3a, ring A4a, ring A5a, ring A5b, ring A5c, ring A5d,ring A6a, ring A6b, ring A6c, ring A6d, ring A6e, ring A7a, ring A7b,ring A7c, ring A7d, ring A7e, ring A7f, ring A7g, ring A7h or ring A7i.More preferred is ring A3a, ring A4a, ring A5a, ring A5b, ring A5c, ringA5d, ring A6a, ring A6b, ring A6c, ring A6d, ring A6e, ring A7a, ringA7b, ring A7c or ring A7d. Even more preferred is ring A3a, ring A4a,ring A5a, ring A6a, ring A6b or ring A7a.

In another embodiment of the present invention, preferred is ring A5a,ring A5b, ring A5c, ring A5d, ring A6a, ring A6b, ring A6c, ring A6d,ring A6e, ring A7a, ring A7b, ring A7c, ring A7d, ring A7e, ring A7f,ring A7g, ring A7h or ring A7i. More preferred is ring A5a, ring A5b,ring A5c, ring A6a, ring A6b, ring A6c, ring A7a, ring A7b, ring A7c orring A7d. Even more preferred is ring A5a, ring A6a, ring A6b or ringA7a.

“Ring B of the spiro-ring AB” refers to a ring B part of theabove-mentioned spiro-ring AB, which is a 5-, 6- or 7-membered saturatedor unsaturated hydrocarbon ring optionally having 1 or 2 double bonds,preferably one double bond in the ring.

n2 is 1, 2, 3 or 4; n3 is 0, 1 or 2; and n2+n3 is 2, 3 or 4. Preferably,n2 is 1, 2 or 3; n3 is 0, 1, or 2; and n2+n3 is 2 or 3. More preferably,n2 is 1 or 2; n3 is 1 or 2; and n2+n3 is 3.

Examples of “the ring B of the spiro-ring AB” are as follows:

Preferred is ring B5a, ring B5b, ring B5c, ring B5d, ring B6a, ring B6b,ring B6c, ring B6d, ring B6e or ring B7a. More preferred is ring B5a,ring B5b, ring B5c, ring B6a, ring B6b, ring B6c or ring B7a. In anotherembodiment of the present invention, preferred is ring B5a, ring B5b,ring B5c, ring B5d, ring B6a, ring B6b, ring B6c, ring B6d or ring B6e.

To be more specific, examples of “the ring B of the spiro-ring AB” areas follows:

Preferred is as follows:

The spiro-ring AB is preferably as follows:

(wherein the symbol represented by the following:

means a single bond or a double bond with the proviso that threecontiguous carbon atoms do not constitute an allene bond represented bythe formula:

C═C═C.)

More preferably, the spiro-ring AB is represented by the following:

and namely, it is a spiro-ring having no double bonds such as ringA4aB5aβ, ring A5aB5aβ, ring A6aB5aβ, ring A7aB5aβ, ring A5aB6aβ, ringA6aB6aβ, ring A7aB6aβ, ring A5aB6aγ or A3aB7aβ; or a spiro-ring havingone double bond such as ring A4aB5bβ, ring A5aB5bβ, ring A5aB5cβ, ringA5aB6bβ, ring A5aB6cβ, ring A6aB6bβ, ring A6aB6cβ, ring A6bB6aβ, ringA7aB6cβ, ring A5aB6cγ or ring A6aB6cγ.

Even more preferred is ring A5aB6aβ, ring A5aB6bβ, ring A5aB6cβ, ringA6aB6aβ, ring A6aB6bβ or ring A6aB6cβ.

As a spiro-ring having no double bonds, ring A5aB6aβ or ring A6aB6aβ isespecially preferable.

As a spiro-ring having one double bond, ring A5aB6bβ, ring A5aB6cβ, ringA6aB6bβ or ring A6aB6cβ is especially preferable.

Similarly, in another embodiment, the spiro-ring AB is preferably acombination of ring A5a, ring A5b, ring A5c, ring A6a, ring A6b, ringA6c, ring A7a, ring A7b, ring A7c or ring A7d with ring B5a, ring B5b,ring B5c, ring B6a, ring B6b or ring B6c. The spiro-ring AB is morepreferably a combination of ring A5a, ring A6a, ring A6b, ring A7a orring A7d with ring B5a, ring B5b, ring B5c, ring B6a, ring B6b or ringB6c.

Even more preferably, the spiro-ring AB is a combination of ring A5awith ring B5a, ring B5b, ring B5c, ring B6a, ring B6b or ring B6c; acombination of ring A6a with ring B5a, ring B5b, ring B5c, ring B6a,ring B6b or ring B6c; a combination of ring A6b with ring B6a; acombination of ring A7a with ring B5a, ring B6a or ring B6c; or acombination of ring A7d with ring B5a, ring B6a or ring B6c.

Similarly, in another embodiment, the spiro-ring AB is more preferably acombination of ring B5a with ring A5a, ring A6a, ring A7a or ring A7d; acombination of ring B5b with ring A5a or ring A6a; a combination of ringB5c with ring A5a or ring A6a; a combination of ring B6a with ring A5a,ring A6a, ring A6b, ring A7a or ring A7d; a combination of ring B6b withring A5a or ring A6a; or a combination of ring B6c with ring A5a, ringA6a, ring A7a or ring A7d.

Further, in another embodiment of the present invention, the spiro-ringAB is preferably a combination of ring A3a, ring A4a, ring A5a, ringA6a, ring A6b, ring A7a or ring A7d with ring B5a, ring B5b, ring B5c,ring B6a, ring B6b, ring B6c, ring B7a or ring B7b. More preferably, thespiro-ring AB is a combination of ring A3a with ring B7a or ring B7b; acombination of ring A4a with ring B5a or ring B5c; a combination of ringA5a with ring B5a, ring B5b, ring B5c, ring B6a, ring B6b or ring B6c; acombination of ring A6a with ring B5a, ring B5b, ring B5c, ring B6a,ring B6b or ring B6c; a combination of ring A6b with ring B6a; acombination of ring A7a with ring B5a, ring B6a or ring B6c; or acombination of ring A7d with ring B5a, ring B6a or ring B6c.

Similarly, in another embodiment, the spiro-ring AB is preferably acombination of ring B5a with ring A5a, ring A6a, ring A7a or ring A7d; acombination of ring B5b with ring A5a or ring A6a; a combination of ringB5c with ring A5a or ring A6a; a combination of ring B6a with ring A5a,ring A6a, ring A6b, ring A7a or ring A7d; a combination of ring B6b withring A5a or ring A6a; a combination of ring B6c with ring A5a, ring A6a,ring A7a, or ring A7d; a combination of ring B7a with ring A3a; or acombination of ring B7b with ring A3a.

“May be substituted by the same or different substituent (s)” means thata spiro-ring AB is non-substituted or substituted by one or more same ordifferent substituents.

The substituent (s) of “the spiro-ring AB” is/are 1 to 5, preferably 1to 3, same or different C₁-C₆ alkyl, hydroxy, oxo or C₁-C₆ alkoxygroups, more preferably 1 to 3 same or different C₁-C₆ alkyl or hydroxygroups. The C₁-C₆ alkyl group is preferably a C₁-C₄ alkyl group.Further, the substituent (s) of the spiro-ring AB is/are even morepreferably 1 to 5 same or different methyl, ethyl, n-propyl, isopropylor hydroxy groups. Especially preferred are 1 to 3 same or differentmethyl, ethyl, n-propyl, isopropyl or hydroxy groups.

Furthermore, a non-substituted spiro-ring AB is preferable.

The substituent (s) of “the ring A of the spiro-ring AB” is/are 1 to 5,preferably 1 to 3, same or different C₁-C₆ alkyl, hydroxy, oxo or C₁-C₆alkoxy groups, more preferably 1 to 3 same or different C₁-C₆ alkyl,hydroxy or oxo groups. The C₁-C₆ alkyl group is preferably a C₁-C₄ alkylgroup. Further, the substituent (s) of the ring A is/are even morepreferably 1 to 5 same or different methyl, ethyl, n-propyl or isopropylgroups. Especially more preferred are 1 to 3 same or different methyl,ethyl, n-propyl or isopropyl groups.

Furthermore, “the ring A of the spiro-ring AB” is preferablynon-substituted.

The substituent (s) of “the ring B of the spiro-ring AB” is/are 1 to 5,preferably 1 to 3, same or different C₁-C₆ alkyl, hydroxy, oxo or C₁-C₆alkoxy groups. Preferred are 1 to 5 (preferably 1 to 3) same ordifferent C₁-C₆ alkyl, hydroxy or oxo groups. More preferred are 1 to 5same or different C₁-C₄ alkyl or hydroxy groups. Even more preferred are1 to 3 same or different C₁-C₄ alkyl or hydroxy groups.

Furthermore, “the ring B of the spiro-ring AB” is preferablynon-substituted.

R¹ is preferably a C₂-C₆ alkynyl group or a C₁-C₆ alkoxy group.

The configuration of the carbon atom bound to R¹ is racemate (RS or(+−)), R, S, (−) or (+), and preferably S or (−).R² is preferably a C₁-C₆ alkyl group, a hydroxy group or a C₁-C₆ alkoxygroup.p is 0, 1, 2 or 3, preferably 0 or 1, more preferably 0.X is preferably a carbon atom.m1 is preferably 0 or 1, more preferably 1.m2 is preferably 0.

The general formula [Ia] is preferably the following:

(wherein each symbol is as defined above).

Similarly, preferred is

(wherein each symbol is as defined above).

More preferred is the general formula [Ia-2] or [Ia-3] in which “thespiro-ring AB” is as follows:

“The benzylic carbon atom” refers to the carbon atom which isrepresented by “C_(A)” as below and substituted by R¹ in the generalformula [Ia] or [I] (i.e., the carbon atom in a methine group):

(wherein each symbol is as defined above).If the carbon atom is a chiral carbon atom, “the chirality at thebenzylic carbon” refers to the chirality of the above-mentioned“benzylic carbon atom”. The chirality is expressed as, for example,racemate, R-isomer, S-isomer, (−)-isomer or (+)-isomer. The same willapply to such a carbon atom in the general formulae [I], [Ia] andintermediates thereof as used in the present description.

“The carbon atom at the spiro junction” refers to the carbon atomrepresented by C* as below among the carbon atoms of the ring B of thespiro-ring AB in the general formula [Ia] or [I]:

(wherein each symbol is as defined above).If the carbon atom is a chiral carbon atom, “the chirality of the carbonat the Spiro junction” refers to the chirality of the above-mentioned“carbon atom at the Spiro junction”. The chirality is expressed as, forexample, racemate, R-isomer, S-isomer, (−)-isomer, (+)-isomer, chiral: Aor chiral: B. The same will apply to such a carbon atom in the generalformulae [I], [Ia] and intermediates thereof as used in the presentdescription.

“A pharmaceutically acceptable salt of the compound represented by thegeneral formula [I] (hereinafter referred to as the compound of thepresent invention or Compound [I])” or “a pharmaceutically acceptablesalt of the compound represented by the general formula [Ia](hereinafter referred to as the compound of the present invention orCompound [Ia])” may be any salt with the proviso that it is a non-toxicsalt formed with the compound of the present invention. For example, inthe case of the compound having a basic group such as an amino group inthe molecule, a salt with an inorganic acid, a salt with an organic acidand a salt with an acidic amino acid can be used. In the case of thecompound having an acidic group such as a carboxyl group and a sulfonicgroup in the molecule, a salt with an inorganic base, a salt with anorganic base and a salt with a basic amino acid, etc. can be used.

Examples of the salt with an inorganic acid include a salt withhydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrobromic acid or the like.

Examples of the salt with an organic acid include a salt with oxalicacid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid,succinic acid, tartaric acid, acetic acid, trifluoroacetic acid,gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid or the like. Examples of the salt with anacidic amino acid include a salt with aspartic acid, glutamic acid orthe like.

Examples of the salt with an inorganic base include a sodium salt, apotassium salt, a calcium salt, a magnesium salt or an ammonium salt.Preferred is a sodium salt, a potassium salt or a calcium salt, and morepreferred is a sodium salt or a calcium salt.

Examples of the salt with an organic base include a salt withmethylamine, diethylamine, trimethylamine, triethylamine, ethanolamine,diethanolamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, dicyclohexylamine,N,N-dibenzylethylenediamine, guanidine, pyridine, picoline, choline,cinchonine, meglumine or the like. Preferred is a salt withethanolamine, diethanolamine, triethanolamine, dicyclohexylamine orN,N-dibenzylethylenediamine.

Examples of the salt with a basic amino acid include a salt with lysine,arginine or the like. Preferred is a salt with lysine.

Each salt can be obtained by reacting the compound represented by thegeneral formula [I] or [Ia] with an inorganic base, an organic base, aninorganic acid, an organic acid or a basic or acidic amino acid inaccordance with a method known per se.

“The solvate” refers to the compound represented by the general formula[I] or [Ia], or a pharmaceutical acceptable salt thereof to which asolvent molecule coordinates, including a hydrate. The solvate ispreferably a pharmaceutically acceptable solvate, and includes, forexample, a monohydrate, a 1/2-hydrate, a dihydrate, a sodium saltmonohydrate, a monomethanolate, a monoethanolate, a 1-propanolate, a2-propanolate, a monoacetonitrilate and a dihydrochloride 2/3 ethanolateof the compound represented by the general formula [I] or [Ia].

The solvate can be obtained by a method known per se.

In addition, there exist various isomers of the compound represented bythe formula [I] or [Ia]. For example, E- and Z-geometric isomers canexist. Also, in the case where a chiral carbon atom is present in themolecule, enantiomers and diastereomers can exist as a stereoisomerbased on the chiral carbon atom. In the case where an axial chirality ispresent in the molecule, there can exist stereoisomers based on theaxial chirality. In some cases, tautomeric isomers also can exist.Accordingly, all these isomers and a mixture thereof are included in thescope of the present invention.

The compound represented by the general formula [I] or [Ia] may belabeled with an isotope such as ³H, ¹⁴C and ³⁵S.

It is preferable that the compound represented by the general formula[I] or [Ia], a pharmaceutically acceptable salt thereof or a solvatethereof is substantially purified. More preferably, the compoundrepresented by the general formula [I] or [Ia], a pharmaceuticallyacceptable salt thereof or a solvate thereof is purified so that it hasa purity of 80% or more.

According to the present invention, a pro-drug of the compoundrepresented by the general formula [I] or [Ia] can be useful as amedicament. “The pro-drug” refers to a derivative of the compound of thepresent invention which has a chemically or metabolically degradablegroup and reveals an original pharmaceutical effect after regaining itsoriginal compound form by, for example, hydrolysis, solvolysis ordegradation under a physiological condition once administered to aliving body. A non-covalently bonded complex and a salt may be alsoincluded. The pro-drug is, for example, used for improving theabsorption rate in oral administration or delivering a drug to thetarget site. A modification site of the compound of the presentinvention may be a highly reactive functional group such as a hydroxygroup, a carboxyl group, an amino group and a mercapto group.

Specifically, a modifying group for a hydroxy group includes an acetylgroup, a propionyl group, an isobutyryl group, a pivaloyl group, apalmitoyl group, a benzoyl group, 4-methylbenzoyl, a dimethylcarbamoylgroup, a dimethylaminomethylcarbonyl group, a sulfo group, an alanylgroup or a fumaryl group. A sodium salt of a 3-carboxybenzoyl or2-carboxyethylcarbonyl group, etc. is also included.

Specifically, a modifying group for a carboxyl group includes a methylgroup, an ethyl group, a propyl group, an isopropyl group, a butylgroup, an isobutyl group, a tert-butyl group, a pivaloyloxymethyl group,a carboxymethyl group, a dimethylaminomethyl group, a 1-(acetyloxy)ethylgroup, a 1-(ethoxycarbonyloxy)ethyl group, a1-(isopropyloxycarbonyloxy)ethyl group, a1-(cyclohexyloxycarbonyloxy)ethyl group, a(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, a benzyl group, a phenylgroup, an o-tolyl group, a morpholino ethyl group, anN,N-diethylcarbamoylmethyl group or a phthalidyl group.

Specifically, a modifying group for an amino group include a tert-butylgroup, a docosanoyl group, a pivaloylmethyloxy group, an alanyl group, ahexylcarbamoyl group, a pentylcarbamoyl group, a3-methylthio-1-(acetylamino)propylcarbonyl group, a1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, atetrahydrofuranyl group or a pyrolidyl methyl group.

In the present invention, the spiro compound represented by thefollowing general formula [IIa] or [II], a pharmaceutically acceptablesalt thereof or a solvate thereof exhibits the same effect as thecompound represented by the general formula [I] or [Ia], apharmaceutically acceptable salt thereof or a solvate thereof, and canbe used like the compound represented by the general formula [I] or[Ia], a pharmaceutically acceptable salt thereof or a solvate thereof.

(wherein each symbol is as defined above.)

A preferable example of the compound represented by the general formula[IIa] is the compound represented by the following formula:

(wherein each symbol is as defined above).Also, each substituent in the general formulae [IIa] and [II] is asdefined in the general formula [I] or [Ia].

The pharmaceutical composition of the present invention can be preparedby appropriately mixing the spiro compound represented by the generalformula [I] or [Ia], a pharmaceutically acceptable salt thereof or asolvate thereof with at least one kind of a pharmaceutically acceptablecarrier and the like in appropriate amounts according to known methodsper se in the art of pharmaceutical preparations. The amount of thecompound represented by the general formula [I] or [Ia], apharmaceutically acceptable salt thereof or a solvate thereof in thepharmaceutical composition is about 0.1 to 100% by weight of the totalweight of the composition, but it varies depending on a dosage form, adose and the like.

Examples of the pharmaceutical composition of the present inventioninclude oral preparations such as tablets, capsules, granules, powders,troches, syrups, emulsions, suspensions, etc. or parenteral preparationssuch as external preparations, suppositories, injections, eye drops,transnasal agents, transpulmonary agents, etc.

“The pharmaceutically acceptable carrier” includes various organic orinorganic carrier substances used commonly as a material forpharmaceutical preparations, and the examples are fillers,disintegrants, binders, fluidizers, lubricants, etc. in the form of asolid preparation, or solvents, solubilizing agents, suspending agents,tonicity agents, buffering agents, soothing agents, etc. in the form ofa liquid preparation. Furthermore, other excipients such aspreservatives, antioxidants, colorants and sweeteners may be used ifneeded.

Examples of the filler include lactose, saccharose, D-mannitol,D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystallinecellulose, carmellose, carmellose calcium, sodium carboxymethyl starch,low substituted hydroxypropyl cellulose, gum arabic and light anhydroussilicic acid.

Examples of the disintegrant include carmellose, carmellose calcium,carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium,crospovidone, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose and crystalline cellulose.

Examples of the binder include hydroxypropyl cellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, saccharose, dextrin,starch, gelatin, carmellose sodium, gum arabic and polyvinylpyrrolidone.

Examples of the fluidizer include light anhydrous silicic acid andmagnesium stearate.

Examples of the lubricant include magnesium stearate, calcium stearate,talc and colloidal silica.

Examples of the solvent include purified water, ethanol, propyleneglycol, macrogol, sesame oil, corn oil and olive oil.

Examples of the solubilizing agent include propylene glycol, D-mannitol,benzyl benzoate, ethanol, triethanolamine, sodium carbonate and sodiumcitrate.

Examples of the suspending agent include benzalkonium chloride,carmellose, hydroxypropyl cellulose, propylene glycol, povidone,methylcellulose and glycerol monostearate.

Examples of the tonicity agent include glucose, D-sorbitol, sodiumchloride and D-mannitol.

Examples of the buffering agent include sodium hydrogen phosphate,sodium acetate, sodium carbonate and sodium citrate.

Examples of the soothing agent include benzyl alcohol.

Examples of the preservative include ethyl parahydroxybenzoate,chlorobutanol, benzyl alcohol, sodium dehydroacetate and sorbic acid.

Examples of the antioxidant include sodium sulfite and ascorbic acid.

Examples of the colorant include a food coloring (e.g. food red No. 2 or3, or food yellow No. 4 or 5, etc.) and β-carotene.

Examples of the sweetener include sodium saccharin, dipotassiumglycyrrhizate and aspartame.

The pharmaceutical composition of the present invention can beadministered orally or parenterally (e.g. topically, rectally,intravenously, etc.) into, not only human, but also the other mammals(e.g. mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, bovine,horse, sheep, monkey, etc.). A dose differs according to the subject,disease, symptom, dosage form, dosing route, etc. For example, when thecomposition is orally administered to an adult patient weighing about 60kg, the dose of the compound represented by the general formula [I] or[Ia] of the present invention, a pharmaceutically acceptable saltthereof or a solvate thereof, which is an effective ingredient, usuallyranges from about 1 mg to 2 g daily. The above-mentioned dose can beadministered at one time or in several divided portions.

The compound represented by the general formula [I] or [Ia], apharmaceutically acceptable salt thereof or a solvate thereof issuitable for treating or preventing a GPR40-related disease.

“The GPR40-related disease” includes diabetes mellitus, hyperglycemia,impaired glucose tolerance, insulin resistance, impaired fastingglucose, diabetic neuropathy, diabetic nephropathy, diabeticretinopathy, ketoacidosis, hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, dyslipemia, hyperlipoproteinemia, metabolicsyndrome, obesity and atherosclerosis. Especially, it is exemplified bydiabetes mellitus, hyperglycemia, impaired glucose tolerance andimpaired fasting glucose.

Diabetes mellitus refers to type 1 and 2 diabetes mellitus, andpreferably type 2 diabetes mellitus.

A suitable subject administered with the compound represented by thegeneral formula [I] or [Ia], a pharmaceutically acceptable salt thereof,a solvate thereof or a pharmaceutical composition containing any of themis preferably a patient with such a GPR40-related disease, mostpreferably a patient with a disease selected from the group consistingof diabetes mellitus, hyperglycemia, impaired glucose tolerance andimpaired fasting glucose.

“Treating”, “being treated” and “treatment” refer to ameliorating orcuring a symptom or a disease and/or a sign associated therewith, andameliorating the same.

“Preventing”, “being prevented” and “prevention” refer to a method fordelaying or preventing the onset of a symptom or a disease and a signassociated therewith, a method for preventing the subject from acquiringa symptom or a disease, or a method for reducing the subject's risk ofacquiring a symptom or a disease.

The compound represented by the general formula [I] or [Ia], apharmaceutically acceptable salt thereof or a solvate thereof is usefulas a medicament for modulating the function of GPR40 (GPR40 agonistmedicament), and particularly as an insulin secretion-promoting agentand a hypoglycemic agent due to its GPR40 agonist activity.

For example, the diagnostic criteria for diabetes mellitus recommendedin Japan, United States and World Health Organization (WHO) are asfollows.

According to the diagnostic criterion for diabetes mellitus issued byJapan Diabetes Society (JDS) in 1999, diabetes mellitus refers to any ofthe following conditions: fasting plasma glucose level (FPG) of 126mg/dl or higher, 2-hour post-load plasma glucose level (2 hPG) in 75 goral glucose tolerance test (OGTT) of 200 mg/dl or higher and basalplasma glucose level of 200 mg/dl or higher.

Also, the case which belongs neither to the above diabetes mellitus andnor to the normal type having a condition of fasting plasma glucoselevel of lower than 110 mg/dl or 2-hour post-load plasma glucose levelin 75 g oral glucose tolerance test (OGTT) of lower than 140 mg/dl isdefined as the borderline type (impaired glucose regulation: IGR).

According to the diagnostic criteria for diabetes mellitus issued by WHOin 1998 and by American Diabetes Association (ADA) in 1997, diabetesmellitus refers to a condition of fasting plasma glucose level of 126mg/dl or higher and 2-hour post-load plasma glucose level in 75 g oralglucose tolerance test of 200 mg/dl or higher.

These criteria also heavily focus on detecting a high-risk diabeticpopulation (prediabetes). The symptoms during transition fromprediabetes to diabetes mellitus include impaired glucose tolerance(IGT), impaired fasting glucose (IFG) and a combination thereof.Impaired glucose tolerance refers to a condition which meets fastingplasma glucose level <126 mg/dl and 2-hour post-load plasma glucoselevel in 75 g oral glucose tolerance test ≧140 mg/dl but <200 mg/dl.Impaired fasting glucose refers to a condition which meets fastingplasma glucose level ≧110 mg/dl but <126 mg/dl and 2-hour post-loadplasma glucose level in 75 g oral glucose tolerance test <140 mg/dl (ADAdefines impaired fasting glucose as a condition which meets fastingplasma glucose level ≧100 mg/dl but <126 mg/dl).

The compound of the present invention, a pharmaceutically acceptablesalt thereof or a solvate thereof can be also used as a medicament forpreventing or treating the diabetes mellitus, borderline diabetesmellitus, impaired glucose tolerance and impaired fasting glucosedetermined by the above-mentioned new criteria. Further, the compound ofthe present invention, a pharmaceutically acceptable salt thereof or asolvate thereof can prevent diabetes mellitus and the progression ofborderline diabetes mellitus, impaired glucose tolerance and impairedfasting glucose into diabetes mellitus.

The compound of the present invention, a pharmaceutically acceptablesalt thereof or a solvate thereof is useful as a medicament for treatingdiabetes mellitus with secondary failure of sulfonylurea therapy. In thetreatment of diabetes mellitus with secondary failure of sulfonylureatherapy, a sulfonylurea compound or a fast-acting insulinsecretion-promoting agent cannot exert insulin secretion-promotingeffect, and therefore its hypoglycemic effect is unsatisfactory. Evenfor the patients with such diabetes mellitus, the compound of thepresent invention, a pharmaceutically acceptable salt thereof or asolvate thereof can be used.

The sulfonylurea compound refers to a compound having a sulfonylureabackbone or a derivative thereof, and includes tolbutamide,glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide,glyclopyramide, glimepiride, glipizide and glybuzole.

The fast-acting insulin secretion-promoting agent refers to a compoundhaving no sulfonylurea backbones and promoting the insulin secretionfrom pancreatic β cells like a sulfonylurea compound, and includes aglinide compound such as repaglinide, senaglinide, nateglinide,mitiglinide or a calcium salt hydrate thereof.

The spiro compound represented by the general formula [I] or [Ia], apharmaceutically acceptable salt thereof or a solvate thereof can beused in combination (sometimes hereinafter referred to combined use)with one or more drugs (sometimes hereinafter referred to drugs incombined use) in a conventional manner in the pharmaceutical field.

The Spiro compound represented by the general formula [I] or [Ia], apharmaceutically acceptable salt thereof or a solvate thereof and thedrug in combined use can be administered without limitation as to thetiming. These may be administered to the subject in the form of acombination preparation, or administered simultaneously or separately ata certain interval. They may be used as a medicament in the form of akit comprising the pharmaceutical composition of the present inventionand the drug in combined use. A dose of the drug in combined use may beemployed in compliance with the dose used in the clinical field and canbe appropriately selected according to the subject, disease, symptom,dosage form, dosing route, dosing duration, combination, etc. The dosingmethod of the drug in combined use is not particularly limited and anymethod may be employed as long as the compound of the present invention,a salt thereof or a solvate thereof, and the drug in combined use arecombined.

The drug in combined use includes

(1) a drug for treating or preventing hyperlipidemia;(2) a drug for treating or preventing obesity;(3) a drug for treating or preventing diabetes mellitus;(4) a drug for treating or preventing diabetes complication; and(5) a drug for treating or preventing hypertension. One to three of theabove-combined drugs can be used in combination with the spiro compoundrepresented by the general formula [I] or [Ia], a pharmaceuticallyacceptable salt thereof or a solvate thereof.

“The drug for treating and/or preventing hyperlipidemia” includes, forexample, apolipoprotein-A1 (Apo-A1) inducer, cholesteryl ester transferprotein (CETP) inhibitor, endothelial lipase inhibitor, HMG-CoAreductase inhibitor, lipoprotein lipase (LPL) activator, microsomaltriglyceride transfer protein (MTP) inhibitor, PPARα receptor agonistand PPARδ receptor agonist.

“The drug for treating and/or preventing obesity” includes, for example,acetyl-CoA carboxylase 1 (ACC1) inhibitor, acetyl-CoA carboxylase 2(ACC2) inhibitor, bombesin receptor subtype 3 (BRS-3) agonist,diacylglycerol acyltransferase (DGAT) inhibitor, glucose-dependentinsulinotropic polypeptide (GIP) receptor antagonist, leptin receptoragonist, melanocortin (MC) receptor agonist, neuropeptide Y5 (NPY5)receptor antagonist, perilipin inhibitor, uncoupling protein (UCP)inducer/activator, 11β-HSD-1 inhibitor, adiponectin receptor agonist,AMP-activated protein kinase (AMPK) activator, PPARγ receptoragonist/antagonist and β3 adrenergic receptor agonist.

“The drug for treating and/or preventing diabetes mellitus” includes,for example, insulin preparation (injection),fructose-1,6-bisphosphatase (FBPase) inhibitor, glucagon receptorantagonist, glucocorticoid receptor antagonist, glucokinase activator,glutamine:fructose-6-phosphate aminotransferase (GFAT) inhibitor,glycogen phosphorylase (GP) inhibitor, glycogen synthase kinase 3(GSK-3) inhibitor, GPR40 agonist, phosphoenolpyruvate carboxykinase(PEPCK) inhibitor, protein tyrosine phosphatase 1B (PTPase 1B)inhibitor, pyruvate dehydrogenase kinase (PDHK) inhibitor, SGLUTinhibitor, SH2 domain-containing inositol phosphatase (SHIP2) inhibitor,dipeptidyl peptidase IV (DPP-IV) inhibitor, tGLP-1 peptide analog,α-glucosidase inhibitor, insulin sensitivity enhancer, sulfonylureareceptor agonist (SU agent), fast-acting insulin secretion-promotingdrug (nateglinide), low-molecular weight agonist of tGLP-1 receptor,oral low-molecular weight insulin preparation, biguanides, 11β-HSD-1inhibitor, adiponectin receptor agonist, AMP-activated protein kinase(AMPK) activator, PPARγ receptor agonist/antagonist and β3 adrenergicreceptor agonist.

“The drug for treating or preventing diabetes complication” includes,for example, advanced glycation end products (AGE) production inhibitor,aldose reductase inhibitor, angiotensin II receptor antagonist,angiotensin-converting enzyme (ACE) inhibitor and protein kinase Cβ (PKCβ) inhibitor.

“The drug for treating or preventing hypertension” includes, forexample, α blocker, β blocker, angiotensin-converting enzyme inhibitor(ACE inhibitor), calcium channel blocker and renin inhibitor.

An exemplary method for preparing the compound of the present inventionwill be hereinafter explained, but the present invention is not limitedthereto. It will be understood that the compound of the presentinvention can be prepared in accordance with a method known per se. Uponthe preparation of the compound of the present invention, the order ofreactions can be changed appropriately. Namely, any step may beperformed first or any substituent may be subjected to the firstreaction as long as it is considered to be reasonable.

Any step to convert a substituent (i.e., conversion or additionalmodification of a substituent, including, for example oxidation orreduction of a substituent) may be optionally inserted between eachstep. A reactive functional group, if any, may be appropriatelyprotected or deprotected. Further, any other reagent than theexemplified reagents can be used appropriately to promote the reactionforward. Also, a reaction can be performed under anhydrous condition(for example, under nitrogen atmosphere).

A compound obtained at each step may be isolated and purified by aconventional method appropriately selected from crystallization,recrystallization, distillation, liquid-liquid separation, columnchromatography and preparative HPLC, etc. or a combination thereof. Insome cases, the next step can be started without isolating or purifyinga compound obtained at each step.

In the preparation methods hereinafter, “room temperature” refers to atemperature of 1 to 40° C. Also in the following formulae, a bondrepresented by the symbol:

means a single bond or a double bond with the proviso that threecontiguous carbon atoms do not constitute an allene bond represented bythe formula:

C═C═C.)

Also, for example, “a compound represented by (General) Formula (1)” canalso be represented as “Compound (1)”.

Preparation Method A

(wherein R^(1′) is a C₁-C₆alkyl group, a C₂-C₆alkenyl group, aC₂-C₆alkynyl group, a phenyl group, a hydroxy group, a five-memberedheteroaryl group which has at least one heteroatom selected from anitrogen atom, an oxygen atom and a sulfur atom, and which may besubstituted by a C₁-C₆alkyl group, or a di(C₁-C₆alkoxy)methyl group);R^(1″) a C₁-C₆alkoxy group, a hydroxy C₁-C₆alkyl group, a C₁-C₆alkoxy(C₁-C₆) alkyl group, —CONR¹¹R¹² (R¹¹ and R¹² are the same or differentand each represents a hydrogen atom or a C₁-C₆ alkyl group), or afive-membered heteroaryl group which has at least one heteroatomselected from a nitrogen atom, an oxygen atom and a sulfur atom, andwhich may be substituted by a C₁-C₆alkyl group;X⁵¹ and X⁵² are the same or different and each represents a hydroxygroup or a leaving group;R⁵¹ is a C₁-C₆alkyl group; and other symbols are as defined above.)

Examples of the Preparation Method A are shown in Preparation Methods A1to A5 below.

Preparation Method A1

Compound (3) can be obtained from Compound (1) and Compound (2)according to the following Step 1 or Step 1′.

Step 1

Compound (3) can be obtained by condensation of Compound (1) in whichX⁵¹ is a hydroxy group and Compound (2) in which X⁵² is a hydroxy groupin a solvent at room temperature or with heat. The reagent is preferably1,1′-(azodicarbonyl)dipiperidine, triphenylphosphine, or the like. Thesolvent is preferably, for example, an ether solvent such astetrahydrofuran.

Step 1′

Compound (3) can be obtained by reaction of Compound (1) in which X⁵¹ isa hydroxy group and Compound (2) in which X⁵² is a leaving group, orCompound (1) in which X⁵¹ is a leaving group and Compound (2) in whichX⁵² is a hydroxy group, in a solvent in the presence of a base at roomtemperature or with heat. The leaving group is preferably a chlorineatom, a bromine atom, an iodine atom or a methanesulfonyloxy group, andmore preferably a chlorine atom, a bromine atom or an iodine atom. Thebase is preferably an alkali metal carbonate such as potassium carbonateor cesium carbonate. The solvent is preferably a polar solvent such asN,N-dimethylformamide.

Preparation Method A2

A compound represented by the general formula [I] can be obtained byhydrolysis of Compound (3) or Compound (3′), in a solvent in thepresence of a base at room temperature or with heat. The base ispreferably an aqueous solution of sodium hydroxide, potassium hydroxide,or the like. The solvent is preferably, for example, an ether solventsuch as tetrahydrofuran, an alcoholic solvent such as methanol, or amixture thereof.

Preparation Method A3

Compound (3′) can be obtained from Compound (3) according to thefollowing method.

Examples of the Preparation Method A3 are shown in Preparation MethodsA3-1 to A3-5 below.

Preparation Method A3-1

Compound (3′) in which R¹ is a hydroxy C₁-C₆alkyl group can be obtainedfrom Compound (3) in which R^(1′) is a di(C₁-C₆alkoxy)methyl groupaccording to the following steps.

Step 1

An aldehyde intermediate can be obtained by deprotection of Compound (3)in which R^(1′) is a di(C₁-C₆alkoxy)methyl group in a solvent underacidic condition at room temperature or with heat. The acid ispreferably camphorsulfonic acid, trifluoroacetic acid, or the like. Thesolvent is preferably a ketone solvent such as acetone.

Step 2

Compound (3′) in which R^(1″) is a hydroxy C₁-C₆alkyl group can beobtained by reduction of the aldehyde intermediate obtained in the aboveStep 1 in a solvent at room temperature or with heat. The reducing agentis preferably sodium borohydride. The solvent is preferably an alcoholicsolvent such as methanol.

Preparation Method A3-2

Compound (3′) in which R^(1″) is a C₁-C₆ alkoxy(C₁-C₆)alkyl group can beobtained by alkylation of Compound (3′) in which R^(1″) is a hydroxyC₁-C₆ alkyl group obtained in the above Preparation Method A3-1 Step 2in a solvent in the presence of abase, and in the presence of anadditive as needed, with cooling or heating. The base is preferably anorganic amine such as N,N-diisopropylethylamine or2,6-di-tert-butyl-4-methylpyridine. The alkylating agent is preferablytri(C₁-C₆alkyl)oxonium tetrafluoroborate or C₁-C₆alkyl bromide oriodide. The tri(C₁-C₆alkyl)oxonium tetrafluoroborate is preferablytrimethyloxonium tetrafluoroborate or triethyloxonium tetrafluoroborate.The C₁-C₆alkyl iodide is preferably methyl iodide, ethyl iodide,n-propyl iodide or isopropyl iodide. When the alkylating agent isC₁-C₆alkyl bromide or iodide, the additive is preferably silver (I)oxide or silver (I) trifluoromethanesulfonate. The solvent is preferablya halogenated hydrocarbon solvent such as chloroform or dichloromethane.

Preparation Method A3-3

Compound (3′) in which R^(1″) is —CONR¹¹R¹² (R¹¹ and R¹² are the same ordifferent and each represents a hydrogen atom or a C₁-C₆alkyl group) canbe obtained from the aldehyde intermediate obtained in the abovePreparation Method A3-1 Step 1 according to the following steps.

Step 1

A carboxylic acid intermediate can be obtained by oxidation of thealdehyde intermediate obtained in the above Preparation Method A3-1 Step1 in a solvent in the presence of an additive at room temperature orwith heat. The oxidant is preferably sodium chlorite, and the additiveis preferably sodium dihydrogen phosphate and 2-methyl-2-butene. Thesolvent is preferably an alcoholic solvent such as tert-butanol, a polarsolvent such as water, or a mixture thereof.

Step 2

Compound (3′) in which R^(1″) is —CONR¹¹R¹² (R¹¹ and R¹² are the same ordifferent and each represents a hydrogen atom or a C₁-C₆ alkyl group)can be obtained by condensation of the carboxylic acid intermediateobtained in the above Step 1 and HN R¹¹R¹² (R¹¹ and R¹² are as definedabove) in the usual manner.

Preparation Method A3-4

Compound (3′) in which R^(1″) is an N—(C₁-C₆alkyl)tetrazole group can beobtained by reaction of Compound (3′) in which R^(1″) is —CONR¹¹R¹² (R¹¹is a hydrogen atom here, and other symbols are as defined above),obtained in the above Preparation Method A3-3 Step 2 in a solvent in thepresence of an azidation agent and a dehydrating agent at roomtemperature or with heat. The dehydrating agent is preferablytrifluoromethanesulfonic anhydride. The azidation agent is preferablysodium azide. The solvent is preferably a polar solvent such asacetonitrile.

Preparation Method A3-5

Compound (3′) in which R^(1″) is a C₁-C₆alkoxy group can be obtainedfrom Compound (3) in which R^(1″) is a hydroxy group in the same manneras in the above Preparation Method A3-2.

Preparation Method A4

Compound (4) can be obtained from Compound (1) and the followingCompound (20):

(wherein symbols are as defined above,)in the same manner as in the above Preparation Method A1 Step or Step1′. The Compound (20) is preferably 4-hydroxybenzaldehyde.

Preparation Method A5

Compound (3) can be obtained from Compound (4) according to thefollowing method.

Examples of the Preparation Method A5 are shown in Preparation MethodsA5-1 to A5-2 below.

Preparation Method A5-1

Compound (3) in which R^(1″) is a hydroxy group can be obtained by aldolreaction of Compound (4) with an acetate represented by the formula:CH₃CO₂R⁵¹ (the symbol is as defined above) in a solvent in the presenceof a base with cooling or at room temperature. The base is preferablylithium diisopropylamide. The solvent is preferably an ether solventsuch as tetrahydrofuran.

Preparation Method A5-2

Compound (3) in which R^(1′) is a hydrogen atom, can be obtained fromCompound (4) according to the following steps.

Step1

An α,β-unsaturated ester intermediate can be obtained by reaction ofCompound (4) with di(C₁-C₆)alkyl phosphonoacetic acid reagent in asolvent in the presence of a base at room temperature or with heat. Thebase is preferably sodium hydride or the like. The di(C₁-C₆)alkylphosphonoacetic acid reagent is preferably triethyl phosphonoacetate.The solvent is preferably an ether solvent such as tetrahydrofuran.

Step2

Compound (3) in which R^(1′) is a hydrogen atom, can be obtained byreduction of the α,β-unsaturated ester intermediate obtained in theabove Step1 in a solvent at room temperature or with heat. The reductionmethod is preferably catalytic hydrogenation in the presence of acatalyst. The catalyst is preferably palladium-carbon. The solvent ispreferably a polar solvent such as ethyl acetate. Optionally,diphenylsulfide or the like can be added as an additive.

Preparation Method B

(wherein Lv₁ is a leaving group, and other symbols are as definedabove.)

Compound (1) means Compound (1a) or Compound (1b), and Compound (1b) canbe produced by converting Compound (1a) into a compound having a leavinggroup by a general method. For example, Compound (1b) can be obtained byreacting Compound (1a) and a halogenating agent in a solvent in thepresence of an additive at room temperature or with heat. Thehalogenating agent is preferably N-bromosuccinimide. The additive ispreferably triphenylphosphine. The solvent is preferably a halogenatedhydrocarbon solvent such as chloroform.

Preparation Method C

(wherein symbols are as defined above.)

Compound (1a) can be obtained from Compound (5) according to thefollowing Preparation Method C1 for preparing Compound (1a-1), Compound(1a-2) or Compound (1a-5) in which the carbon atom at the spiro junctionof the ring B of the spiro-ring AB to which a side chain (CH₂)_(m1)OHbinds is an sp² carbon atom; or the following Preparation Method C2 forpreparing Compound (1a-6), Compound (1a-7), Compound (1a-8) or Compound(1a-9) in which the same carbon atom at the spiro junction is an sp³carbon atom. Examples are shown in Preparation Methods C1 to C2 below.

Preparation Method C1

(wherein symbols are as defined above.)

Examples of the Preparation Method C1 are shown in Preparation MethodsC1-1 to C1-3 below.

Preparation Method C1-1

When n3 is 1 in Compound (1a-1) (in the case of Compound (1a-1a)):

(wherein R¹⁰⁰ is a C₁-C₆alkyl group, Lv₂ is a leaving group, and othersymbols are as defined above.)

Step 1

Compound (5-1a) can be obtained by reaction of Compound (5-1) withdi(C₁-C₆alkyl) carbonate in a solvent in the presence of abase at roomtemperature or with heat. The di(C₁-C₆alkyl) carbonate is preferablydimethyl carbonate. The base is preferably sodium hydride, potassiumtert-butoxide, or the like. The solvent is preferably an ether solventsuch as tetrahydrofuran.

Step 2

Compound (5-1b) can be obtained by reaction of Compound (5-1a) with areducing agent such as sodium borohydride in a solvent at roomtemperature or with heat, or by catalytic reduction of Compound (5-1a)with a catalyst such as platinum oxide in an atmosphere of hydrogen. Thesolvent is preferably an ether solvent such as tetrahydrofuran, analcoholic solvent such as methanol, or a mixture thereof.

Step 3

Compound (5-1c) can be obtained by reaction of Compound (5-1b) withmethanesulfonyl chloride or the like in a solvent under basic conditionat room temperature or with heat. The base is preferably an organic basesuch as triethylamine or pyridine. The solvent is preferably ahalogenated hydrocarbon solvent such as chloroform. Optionally,4-dimethylaminopyridine or the like can be added as an additive.

Step 4 Compound (5-1d) can be obtained by reaction of Compound (5-1c) ina solvent under basic condition at room temperature or with heat. Thebase is preferably an organic base such as1,8-diazabicyclo[5.4.0]undec-7-ene. The solvent is preferably an ethersolvent such as tetrahydrofuran.

Step 5

Compound (1a-1a) can be obtained by reduction of Compound (5-1d) in asolvent with cooling or at room temperature. The reducing agent ispreferably diisobutylaluminum hydride. The solvent is preferably anether solvent such as tetrahydrofuran.

Preparation Method C1-2

When n2 is 2 and n3 is 1 in Compound (1a-2) (in the case of Compound(1a-2a)):

(wherein symbols are as defined above.)

Step 1

Compound (5-2a) can be obtained by reaction of Compound (5-2) withdi(C₁-C₆alkyl) carbonate in a solvent in the presence of a base at roomtemperature or with heat. The di(C₁-C₆alkyl) carbonate is preferablydimethyl carbonate. The base is preferably sodium hydride, or the like.The solvent is preferably an ether solvent such as tetrahydrofuran.

Step 2

Compound (5-2b) can be obtained by reaction of Compound (5-2a) with areducing agent such as sodium borohydride in a solvent at roomtemperature or with heat. The solvent is preferably an ether solventsuch as tetrahydrofuran, an alcoholic solvent such as methanol, or amixture thereof.

Step 3

Compound (5-2c) can be obtained by reaction of Compound (5-2b) withmethanesulfonyl chloride or the like in a solvent under basic conditionat room temperature. The base is preferably an organic base such astriethylamine or pyridine. The solvent is preferably a halogenatedhydrocarbon solvent such as chloroform. Optionally,4-dimethylaminopyridine or the like can be added as an additive.

Step 4

Compound (5-2d) can be obtained by reaction of Compound (5-2c) in asolvent under basic condition at room temperature or with heat. The baseis preferably an organic base such as1,8-diazabicyclo[5.4.0]undec-7-ene. The solvent is preferably an ethersolvent such as tetrahydrofuran.

Step 5

Compound (1a-2a) can be obtained by reduction of Compound (5-2d) in asolvent with cooling or at room temperature. The reducing agent ispreferably diisobutylaluminum hydride. The solvent is preferably anether solvent such as tetrahydrofuran.

Preparation Method C1-3

When n2 is 1 and n3 is 2 in Compound (1a-2) (in the case of Compound(1a-5)):

(wherein symbols are as defined above.)

Step 1

Compound (5-3a) can be obtained by reaction of Compound (5-2) with acyanating agent in the presence of an additive in a solvent at roomtemperature or with heat. The cyanating agent is preferablytrimethylsilylcyanide. The additive is preferably tetra-n-butylammoniumfluoride. The solvent is preferably an ether solvent such astetrahydrofuran.

Step 2

Compound (5-3b) can be obtained by reaction of Compound (5-3a) with achlorinating agent in a solvent in the presence of a base at roomtemperature or with heat. The base is preferably pyridine. Thechlorinating agent is preferably thionyl chloride. The solvent ispreferably an ether solvent such as tetrahydrofuran.

Step 3

Compound (5-3c) can be obtained by reaction of Compound (5-3b) in asolvent under acidic condition at room temperature or with heat. Theacid is preferably concentrated sulfuric acid. The solvent is preferablyan alcoholic solvent such as ethanol.

Step 4

Compound (1a-5) can be obtained by reaction of Compound (5-3c) in thesame manner as in the Preparation Method C1-1 Step 5.

Preparation Method C2

(wherein symbols are as defined above.)

Examples of the Preparation Method C2 are shown in Preparation MethodsC2-1 to C2-3 below.

Compound (1a-6) in which the carbon atom at the spiro junction of thering B of the spiro-ring AB to which a side chain (CH₂)_(m1)OH binds isan sp³ carbon atom, can be obtained by the following preparation methodsas well as by reducing the compound obtained in the above PreparationMethod C1, namely C1-1, C1-2 or C1-3 (i.e., Compound (1a-1a), Compound(1a-2a) or Compound (1a-5)) by catalytic hydrogenation reaction.

Preparation Method C2-1

When m₁ is 0 in Compound (1a-6) (in the case of Compound (1a-7)):

(wherein symbols are as defined above.)

Compound (1a-7) can be obtained by reaction of Compound (5) with areducing agent such as sodium borohydride in a solvent at roomtemperature or with heat. The solvent is preferably an alcoholic solventsuch as methanol.

Preparation Method C2-2

When m₁ is 1 in Compound (1a-6) (in the case of Compound (1a-8)):

(wherein symbols are as defined above.)

Compound (1a-8) can be obtained through the following steps.

Step 1

Compound (5-4a) can be obtained by reaction of Compound (5) with adiazophosphonate compound in a solvent in the presence of a base at roomtemperature or with heat. The diazophosphonate compound is preferablydimethyl(1-diazo-2-oxo-propyl)phosphonate. The base is preferably analkali metal carbonate such as potassium carbonate. The solvent ispreferably an alcoholic solvent such as methanol.

Step 2

Compound (5-4b) can be obtained by reaction of the above Compound (5-4a)in a solvent under acidic condition at room temperature. The acid ispreferably dilute aqueous hydrochloric acid solution. The solvent ispreferably a polar solvent such as acetonitrile.

Step 3

Compound (1a-8) can be obtained by reaction of the above Compound (5-4b)with a reducing agent such as sodium borohydride in a solvent at roomtemperature or with heat. The solvent is preferably an alcoholic solventsuch as methanol.

Preparation Method C2-3

When m₁ is 2 in Compound (1a-6) (in the case of Compound (1a-9)):

(wherein symbols are as defined above.)

Compound (1a-9) can be obtained through the following steps.

Step 1

Compound (5-5a) can be obtained by Horner-Emmons reaction of Compound(5) in a solvent in the presence of a base at room temperature or withheat. The base is preferably sodium tert-butoxide. The solvent ispreferably an aromatic hydrocarbon solvent such as toluene.

Step 2

Compound (5-5b) can be obtained by reduction of the above Compound(5-5a) in a solvent at room temperature. The reduction method ispreferably catalytic hydrogenation in the presence of a catalyst. Thecatalyst is preferably palladium-carbon. The solvent is preferably analcoholic solvent such as ethanol.

Step 3

Compound (1a-9) can be obtained by reduction of the above Compound(5-5b) in a solvent with cooling or at room temperature. The reducingagent is preferably lithium aluminum hydride, or the like. The solventis preferably an ether solvent such as tetrahydrofuran.

Preparation Method D

(wherein symbols are as defined above.)

Compound (5) can be obtained according to the following PreparationMethod D1 for forming a ring A in a compound having the ring B of aspiro-ring AB, or the following Preparation Method D2 for forming a ringB in a compound having the ring A of a spiro-ring AB. Examples are shownin Preparation Methods D1 to D2 below.

Preparation Method D1

Examples of the Preparation Method D1 are shown in Preparation MethodsD1-1 to D1-2 below.

Preparation Method D1-1

(wherein n2″ is 0, 1 or 2, and other symbols are as defined above.)

Step 1

Compound (5b) can be obtained by reaction of Compound (6b) withL₁-C₂-C₆alkylene-L₂ (L₁ and L₂ are the same or different and eachrepresents a leaving group) in a solvent in the presence of a base atroom temperature or with heat. The base is preferably potassiumtert-butoxide. The L₁-C₂-C₆alkylene-L₂ is preferably L-C₂-C₆alkylene-L(L is preferably a halogen atom such as a chlorine atom or a bromineatom). The solvent is preferably an aromatic hydrocarbon solvent such astoluene. Optionally, ultrasound can be used for reaction.

Preparation Method D1-2

(wherein R is a C₁-C₆alkyl group, q1 is 1 or 2, q2 is 1 or 2, and othersymbols are as defined above.)

Step 1

Compound (6c-1) can be obtained by Grignard reaction of Compound (6c) ina solvent with cooling or at room temperature. The solvent is preferablyan ether solvent such as tetrahydrofuran.

Step 2

Compound (6c-2) can be obtained by Grignard reaction of Compound (6c-1)in a solvent in the presence of an additive at room temperature or withheat. The additive is preferably a copper halide such as copper (I)iodide or an alkali metal halide such as lithium bromide. The solvent ispreferably an ether solvent such as tetrahydrofuran.

Step 3

Compound (5c) can be obtained by reaction of Compound (6c-2) in asolvent in the presence of a catalyst at room temperature or with heat.The catalyst is preferably a Grubbs catalyst such asbenzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine) ruthenium. The solvent ispreferably an aromatic hydrocarbon solvent such as toluene.

Preparation Method D2

Examples of the Preparation Method D2 are shown in Preparation MethodsD2-1 to D2-3 below.

Preparation Method D2-1

(wherein n1″ is 2, 3, 4 or 5, and other symbols are as defined above.)

Step 1

Compound (6a-1) can be obtained by reaction of Compound (6a) with methylvinyl ketone in a solvent in the presence of an acid catalyst at roomtemperature or with heat. The acid catalyst is preferably concentratedsulfuric acid. The solvent is preferably an aromatic hydrocarbon solventsuch as toluene.

Step 2

Compound (5a) can be obtained by reduction of Compound (6a-1) in asolvent at room temperature. The reduction method is preferablycatalytic hydrogenation in the presence of a catalyst. The catalyst ispreferably palladium-carbon. The solvent is preferably an ether solventsuch as tetrahydrofuran.

Preparation Method D2-2

(wherein n1′ is 2, 3 or 4, and other symbols are as defined above.)

Step 1

Compound (7-1) can be obtained by oxidation of Compound (5a) obtained inthe Preparation Method D2-1 in a solvent under basic condition at roomtemperature or with heat. The base is preferably sodium hydroxide, andthe oxidant is preferably potassium permanganate. The solvent ispreferably a polar solvent such as water.

Step 2

Compound (7-2) can be obtained by reaction of Compound (7-1) in asolvent in the presence of an alkylating agent under basic condition atroom temperature or with heat. The base is preferably an alkali metalcarbonate such as potassium carbonate or cesium carbonate. Thealkylating agent is preferably benzyl bromide. The solvent is preferablya polar solvent such as acetonitrile or N,N-dimethylformamide.

Step 3

Compound (5e) can be obtained by decarboxylation of Compound (7-2) in asolvent by a general method. For example, Compound (5e) can be obtainedby hydrolyzing Compound (7-2) and subsequent heating.

Meanwhile, Compound (la-3) in which n1 is 2, 3 or 4, can be obtained byreaction of Compound (7-2) obtained above in the same manner as in thePreparation Method C1-1 Steps 2 to 5.

(wherein symbols are as defined above.)

Preparation Method D2-3

(wherein n1′″ is 2 or 3, R⁵² is a C₁-C₆alkyl group, and other symbolsare as defined above.)

Step 1

Compound (8-1) can be obtained by reaction of Compound (6a) with2-hydroxy-3-butenoic acid methyl ester in a solvent in the presence ofan acid catalyst at room temperature or with heat. The acid catalyst ispreferably p-toluenesulfonic acid or the like. The solvent is preferablyan aromatic hydrocarbon solvent such as toluene.

Step 2

Compound (8-2) can be obtained by reaction of Compound (8-1) withtriethylsilane in a solvent in the presence of a catalyst at roomtemperature or with heat. The catalyst is preferablytris(triphenylphosphine)rhodium (I) chloride. The solvent is preferablyan aromatic hydrocarbon solvent such as toluene.

Step 3

Compound (8-3) can be obtained by deprotection of Compound (8-2) in theusual manner.

Compound (5f) can be obtained by reaction of Compound (8-3) obtainedabove in the same manner as in the Preparation Method C1-1 Step 3 toStep 5.

Preparation Method E

Compound (2) in the Preparation Method A can be obtained as thefollowing Compound (2a), (2b), (2c) or (2d).

Examples of the Preparation Method E are shown in Preparation Methods E1to E3 below.

Preparation Method E1

Step 1

Compound (9-1) can be obtained by reaction of 4-hydroxybenzaldehyde withMeldrum's acid in a solvent at room temperature or with heat. Thesolvent is preferably a polar solvent such as water.

Step 2

Compound (9-2) can be obtained by reaction of Compound (9-1) with1-propynylmagnesium bromide in a solvent with cooling or at roomtemperature. The solvent is preferably an ether solvent such astetrahydrofuran.

Step 3

Compound (9-3) can be obtained by heating Compound (9-2) in a solvent.The solvent is preferably a ketone solvent such as 3-pentanone, a polarsolvent such as water, or a mixture thereof.

Step 4

Optically active Compound (9-4) can be obtained by reaction of Compound(9-3) with an optically active basic compound in a solvent followed byrecrystallization and desalination in the usual manner. The solvent ispreferably an alcoholic solvent such as 2-propanol. The optically activebasic compound is preferably (1S,2R)-1-amino-2-indanol or(S)-α-methylbenzylamine.

Step 5

Compound (2a) can be obtained by reaction of Compound (9-4) with analkylating agent in a solvent with cooling or at room temperature. Thealkylating agent is preferably trimethylsilyldiazomethane, or the like.The solvent is preferably an aromatic hydrocarbon solvent such astoluene, an alcoholic solvent such as methanol, or a mixture thereof.

Compound (2a), which is racemate, can be obtained from Compound (9-3) byperforming this Step.

Preparation Method E2

Compound (2b) or (2c) can be obtained according to the following methodsas well as the Preparation Method E1.

An example of the Preparation Method E2 is shown in Preparation MethodE2-1 below.

Preparation Method E2-1

(wherein X⁵³ is a hydroxy protecting group, R⁵³ is a C₂-C₆alkynyl group,a phenyl group, or a five-membered heteroaryl group which has at leastone heteroatom selected from a nitrogen atom, an oxygen atom and asulfur atom, and which may be substituted by a C₁-C₆alkyl group (forexample, a 2-oxazolyl group); R⁵⁴ is a C₁-C₆alkyl group, a C₂-C₆alkenylgroup, or a di(C₁-C₆alkoxy) methyl group; R⁵⁵ is a C₁-C₆alkyl group, aC₂-C₆alkenyl group, a C₂-C₆alkynyl group, a phenyl group, afive-membered heteroaryl group which has at least one heteroatomselected from a nitrogen atom, an oxygen atom and a sulfur atom, andwhich may be substituted by a C₁-C₆alkyl group (for example, a2-oxazolyl group) or a di(C₁-C₆alkoxy)methyl group; and other symbolsare as defined above.)

Step 1

Compound (10-2) can be obtained by reaction of Compound (10-1) withMeldrum's acid in a solvent in the presence of an acid catalyst and anadditive at room temperature or with heat. The acid is preferably aceticacid. The additive is preferably pyrrolidine. The solvent is preferablyan aromatic hydrocarbon solvent such as toluene.

Step 2

Compound (10-3) can be obtained by reaction of Compound (10-2) with anucleophilic agent in a solvent with cooling or at room temperature. Thenucleophilic agent is preferably C₂-C₆alkynylmagnesium bromide,phenylmagnesium bromide, or the like. The solvent is preferably an ethersolvent such as tetrahydrofuran.

Step 3

Compound (10-4) can be obtained by heating Compound (10-3) in a solvent.The solvent is preferably an alcoholic solvent such as ethanol, a polarsolvent such as pyridine, or a mixture thereof.

Step 5

Compound (2b) can be obtained by deprotection of X⁵³, which is a hydroxyprotecting group in Compound (10-4) or Compound (10-5), in the usualmanner. For example, when the protecting group is a tetrahydropyranylgroup, the compound can be obtained by reaction of Compound (10-4) orCompound (10-5) in a solvent in the presence of an acid catalyst at roomtemperature or with heat. The acid is preferably camphorsulfonic acid.The solvent is preferably an alcoholic solvent such as ethanol.

Step 6

Compound (2c) can be obtained by reaction of Compound (2b) with ahalogenating agent in a solvent in the presence of an additive at roomtemperature or with heat. The halogenating agent is preferablyN-bromo-succinimide. The additive is preferably triphenylphosphine. Thesolvent is preferably a halogenated hydrocarbon solvent such aschloroform.

Step 4

Compound (10-5) can be obtained from Compound (10-4) according to thefollowing methods.

Step 4-1

Compound (10-5) in which R⁵⁴ is a C₁-C₆alkyl group can be obtained byreduction of Compound (10-4) in which R⁵³ is a C₂-C₆alkynyl group in asolvent at room temperature. The reduction method is preferablycatalytic hydrogenation, and the catalyst is preferablypalladium-carbon. The solvent is preferably an ether solvent such astetrahydrofuran, an alcoholic solvent such as methanol, or a mixturethereof.

Step 4-2

Compound (10-5) in which R⁵⁴ is a C₂-C₆alkenyl group can be obtained byreduction of Compound (10-4) in which R⁵³ is a C2-C6alkynyl group in asolvent at room temperature. The reduction method is preferablycatalytic hydrogenation, and the catalyst is preferably palladium-bariumsulfate. The solvent is preferably an ether solvent such astetrahydrofuran, an alcoholic solvent such as methanol, or a mixturethereof.

Step 4-3

Compound (10-5) in which R⁵⁴ is a di(C₁-C₆alkoxy)methyl group, can beobtained from Compound (10-5) in which R⁵⁴ is a C₂-C₆alkenyl group,through the following steps.

Step 4-3-1

Compound (10-5) in which R⁵⁴ is an aldehyde group can be obtained bytwo-step oxidation of Compound (10-5) in which R⁵⁴ is a C₂-C₆alkenylgroup in a solvent in the presence of a base at room temperature. Thebase is preferably 2,6-lutidine. The oxidant for the first step ispreferably osmium tetroxide, and the oxidant for the second step ispreferably sodium periodate. The solvent is preferably an ether solventsuch as 1,4-dioxane, a polar solvent such as water, or a mixturethereof.

Step 4-3-2

Compound (10-5) in which R⁵⁴ is a di(C₁-C₆alkoxy)methyl group can beobtained by reaction of Compound (10-5) in which R⁵⁴ is an aldehydegroup, obtained in the above Step 4-3-1, in a solvent in the presence ofan acid catalyst at room temperature or with heat. The acid ispreferably camphorsulfonic acid. The solvent is preferably an alcoholicsolvent such as methanol.

Preparation Method E3

Compound (9-4′) or Compound (2d) can be obtained by the same reaction asin the Preparation Method E1-1 using (1R,2S)-1-amino-2-indanol or(R)-α-methylbenzylamine as an optically active basic compound in Step 4.

Preparation Method As of a compound represented by the general formula[Ia] (Preparation Method A1s, A2s, A3s, A4s and A5s) can be performed inthe same manner as in Preparation Method A of a compound represented bythe above general formula [I] (Preparation Method A1, A2, A3, A4 andA5), respectively.

Preparation Method As

(wherein symbols are as defined above, and in Preparation Method A4s,the following Compound (20s):

(wherein symbols are as defined above) can be used.)

When X is a nitrogen atom and m₂ is 0 in the general formula [Ia], thePreparation Method A1s below is preferable to the above PreparationMethod A1.

Preparation Method A1s Step 1

Compound (3s) in which X in the general formula [Ia] is a nitrogen atom,can be obtained by reaction of Compound (1s) in which X⁵¹ is a hydroxygroup and Compound (2s) in which m₂ is 0 and X⁵² is a bromine atom or aniodine atom, in a solvent in the presence of a base and an additive atroom temperature or with heat. The base is preferably cesium carbonate.The additive is preferably palladium(II) acetate,2-(di-tert-butylphosphino)-1,1′-binaphthyl or the like. The solvent is,for example, preferably an aromatic hydrocarbon solvent such as toluene.

Preparation Method Es

Compound (2s) in the Preparation Method As can be obtained as thefollowing Compound (2s-a), Compound (2s-b), Compound (2s-c) or Compound(2s-d). These compounds can be obtained in the same manner as in theabove Preparation Method E (Preparation Method E1, E2 or E3).

Examples of the Preparation Method Es are shown in Preparation MethodsEs1 to Es3 below.

Preparation Method Es1

(wherein symbols are as defined above.)

Preparation Method Es2

(wherein symbols are as defined above.)

Preparation Method Es3

(wherein symbols are as defined above.)

EXAMPLE

The preparation method for the compound of the present invention will behereinafter explained in detail with examples provided, but the presentinvention is not limited thereto.

In the following examples, “room temperature” refers to a temperature of1 to 40° C. In the examples, “%” refers to % by weight unless otherwisespecified.

Example 1 Preparation of(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

To a solution of cyclohexanecarbaldehyde (10.7 mL) in toluene (100 mL)were added successively methyl vinyl ketone (15 mL) and concentratedsulfuric acid (0.1 mL). The reaction mixture was stirred at roomtemperature for 1 hour and then heated under reflux while stirring for 4hours. After cooling down to room temperature, saturated aqueous sodiumbicarbonate solution was added to the reaction mixture, followed byseparation of the organic layer. Then, after the aqueous layer wasextracted with toluene, the organic layers were combined, washed withsaturated brine, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane (volumeratio)=1:20 to 1:12) to give spiro[5.5]undec-1-en-3-one (8.9 g).

¹H-NMR (CDCl₃) δ: 1.63-1.45 (10H, m), 1.92 (2H, t, J=6.5 Hz), 2.44 (2H,t, J=6.5 Hz), 5.89 (1H, d, J=10.2 Hz), 6.85 (1H, d, J=10.2 Hz).

Step 2

To a solution of spiro[5.5]undec-1-en-3-one (8.9 g) obtained in Step 1in tetrahydrofuran (360 mL) was added 5% palladium carbon (0.89 g),followed by stirring the reaction mixture at room temperature in anatmosphere of hydrogen under normal pressure for 2 hours. Then, thereaction mixture was filtered through Celite and the filtrate wasconcentrated to obtain spiro[5.5]undecan-3-one (9.3 g).

¹H-NMR (CDCl₃) δ: 1.54-1.43 (10H, m), 1.71 (4H, t, J=7.2 Hz), 2.33 (4H,t, J=7.2 Hz).

Step 3

To a solution of dimethyl carbonate (17.9 g) in tetrahydrofuran (130 mL)were added 60% sodium hydride (9.9 g) and potassium tert-butoxide (0.14g). To the mixture was added a solution of spiro[5.5]undecan-3-one (20.6g) obtained in the same manner as in Step 2 in tetrahydrofuran (120 mL)at 85° C. over 2 hours, followed by stirring the reaction mixture at 85°C. for 1.5 hours. After cooling down to room temperature and adding 15%aqueous acetic acid solution (94.2 mL), the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried and concentrated to give3-oxo-spiro[5.5]undecane-2-carboxylic acid methyl ester (29.6 g).

¹H-NMR (CDCl₃) δ: 1.26-1.53 (14H, brm), 2.07 (2H, s), 2.26 (2H, t, J=6.7Hz), 3.76 (3H, s), 12.13 (1H, s).

Step 4

To a solution of 3-oxo-spiro[5.5]undecane-2-carboxylic acid methyl ester(29.6 g) obtained in Step 3 in a mixed solvent of methanol (200mL)-tetrahydrofuran (50 mL), sodium borohydride (4.67 g) was added inthree portions under ice-cooling, followed by stirring the reactionmixture under ice-cooling for 1 hour. Then, after addition of 1N aqueoushydrochloric acid solution to the reaction mixture, the resultinginsolubles were filtered off. Methanol in the filtrate was evaporatedoff in vacuo, followed by extraction with ethyl acetate. The organiclayer was washed with saturated brine, dried and concentrated. Theresidue was purified by column chromatography on silica gel (ethylacetate:hexane (volume ratio)=1:10 to 1:3) to givetrans-3-hydroxy-spiro[5.5]undecane-2-carboxylic acid methyl ester (4.15g) and cis-3-hydroxy-spiro[5.5]undecane-2-carboxylic acid methyl ester(4.9 g).

¹H-NMR (trans-isomer, CDCl₃) δ: 1.05-1.25 (3H, m), 1.37-1.52 (10H, m),1.68-1.76 (1H, m), 1.77-1.85 (1H, m), 1.90-1.97 (1H, m), 2.44-2.51 (1H,m), 2.74 (1H, brs), 3.72 (3H, s), 3.74-3.80 (1H, m).

¹H-NMR (cis-isomer, CDCl₃) δ: 1.23-1.31 (3H, m), 1.67-1.36 (11H, m),1.69-1.77 (2H, m), 2.58 (1H, td, J=8.6, 2.3 Hz), 3.08 (1H, brs), 3.71 (3H, s), 4.16-4.20 (1H, m).

Step 5

To a solution of trans-3-hydroxy-spiro[5.5]undecane-2-carboxylic acidmethyl ester (2.0 g) obtained in the same manner as in Step 4 inchloroform (40 mL) were added successively triethylamine (1.7 mL) andmethanesulfonyl chloride (0.75 mL) under ice-cooling, followed bystirring the reaction mixture at room temperature for 1.5 hours. Then,to the reaction mixture was added saturated aqueous sodium bicarbonatesolution, followed by extraction with chloroform. The organic layer wasdried and concentrated to givetrans-3-methanesulfonyloxy-spiro[5.5]undecane-2-carboxylic acid methylester (3.0 g).

¹H-NMR (CDCl₃) δ: 1.14-1.31 (5H, m), 1.40-1.46 (8H, brm), 1.72-1.81 (2H,m), 1.95 (1H, d, J=13.2 Hz), 2.17-2.23 (1H, m), 2.77 (1H, ddd, J=5.0,13.2, 11.4 Hz), 3.00 (3H, s), 3.72 (3H, s).

Step 5′

To a solution of cis-3-hydroxy-spiro[5.5]undecane-2-carboxylic acidmethyl ester (1.2 g) obtained in the same manner as in Step 4 inchloroform (25 mL) were added successively pyridine (0.6 mL),4-dimethylaminopyridine (32 mg) and methanesulfonyl chloride (1.85 mL)under ice-cooling, followed by stirring the reaction mixture at roomtemperature for 1.5 hours. Then, to the reaction mixture was addedsaturated aqueous sodium bicarbonate solution, followed by extractionwith chloroform twice. The organic layer was dried and concentrated togive cis-3-methanesulfonyloxy-spiro[5.5]undecane-2-carboxylic acidmethyl ester (1.7 g).

¹H-NMR (CDCl₃) δ: 1.27-1.60 (10H, brm), 1.65 (2H, d, J=8.5 Hz),1.70-1.76 (1H, m), 1.84 (1H, dt, J=15.1, 2.2 Hz), 2.13 (1H, dd, J=15.1,3.2 Hz),2.58 (1H, td, J=8.5, 2.2 Hz), 2.69 (1H, dt, J=13.1, 3.2 Hz),3.00 (3H, s), 3.07-3.09 (1H, m), 3.72 (3H, s).

Step 6

To a solution oftrans-3-methanesulfonyloxy-spiro[5.5]undecane-2-carboxylic acid methylester (3.0 g) obtained in Step 5 in tetrahydrofuran (20 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (2.65 mL), followed by stirring thereaction mixture at 70° C. for 6 hours. After cooling down to roomtemperature and adding 2N aqueous hydrochloric acid solution, thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried and concentrated to givespiro[5.5]undec-2-ene-2-carboxylic acid methyl ester (1.9 g).

¹H-NMR (CDCl₃) δ: 1.23-1.37 (4H, m), 1.41-1.50 (8H, m), 2.10-2.13 (2H,m), 2.16-2.22 (2H, m), 3.74 (3H, s), 6.94-6.96 (1H, m).

Step 6′

Cis-3-methanesulfonyloxy-spiro[5.5]undecane-2-carboxyl is acid methylester (1.7 g) obtained in Step 5′ was subjected to the reaction in thesame condition as in Step 6, to give spiro[5.5]undec-2-ene-2-carboxylicacid methyl ester (0.42 g).

Step 7

To a solution of spiro[5.5]undec-2-ene-2-carboxylic acid methyl ester(1.9 g) obtained in the same manner as in Step 6 or 6′ intetrahydrofuran (40 mL) was added dropwise a 1M toluene solution ofdiisobutylaluminum hydride (21 mL) under argon atmosphere at −70° C.,followed by stirring the reaction mixture at −70° C. for 1 hour. Then,after addition of 2N aqueous hydrochloric acid solution, the reactionmixture was heated up to room temperature and extracted with ethylacetate. The organic layer was washed with saturated brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:4) to givespiro[5.5]undec-2-en-2-yl-methanol (1.59 g).

¹H-NMR (CDCl₃) δ: 1.22-1.35 (4H, m), 1.40-1.49 (8H, m), 1.85-1.88 (2H,m), 2.01-2.07 (2H, m), 3.98 (2H, d, J=4.9 Hz), 5.61-5.65 (1H, m).

Step 8

To a solution of spiro[5.5]undec-2-en-2-yl-methanol (0.45 g) obtained inthe same manner as in Step 7 in tetrahydrofuran (7 mL) were addedsuccessively (S)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester (0.73g) obtained in Substep 5 described below, triphenylphosphine (0.92 g)and 1,1′-azobis(N,N-dimethylformamide) (0.6 g), followed by stirring thereaction mixture at room temperature for 4 hours. Then, the reactionmixture was concentrated and the residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:4)to give (S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (0.82 g).

¹H-NMR (CDCl₃) δ: 1.24-1.34 (5H, m), 1.40-1.46 (7H, m), 1.83 (3H, d,J=2.3 Hz), 1.90 (2H, s), 2.04 (2H, s), 2.64 (1H, dd, J=15.1, 7.1 Hz),2.75 (1H, dd, J=15.1, 8.3 Hz), 3.66 (3H, s), 4.02-4.09 (1H, m), 4.34(2H, s), 5.73 (1H, s), 6.85 (2H, d, J=8.7 Hz), 7.26 (2H, d, J=8.7 Hz).

Step 9

To a solution of(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (0.82 g) obtained in Step 8 in a mixed solvent oftetrahydrofuran (4 mL)-methanol (4 mL) was added 2N aqueous sodiumhydroxide solution (2 mL), followed by stirring the reaction mixture atroom temperature for 14 hours. Then, after addition of 1N aqueoushydrochloric acid solution, the reaction mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedand concentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:1) to give(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid(0.77 g) as the desired compound.

Substep 1

To a suspension of 4-hydroxybenzaldehyde (35 g) in water (300 mL) heatedup to 75° C. was added a suspension of Meldrum's acid (43.4 g) in water(300 mL), followed by stirring the reaction mixture successively at 75°C. for 8.5 hours, at room temperature for 14 hours and under ice-coolingfor 2 hours. The resulting crystal was filtered, washed with ice-coldwater and dried in vacuo to give5-(4-hydroxybenzylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (47.3 g).

¹H-NMR (DMSO-d₆) δ: 1.71 (6H, s), 6.89 (2H, d, J=8.8 Hz), 8.17 (2H, d,J=8.8 Hz), 8.25 (1H, s), 10.93 (1H, s).

Substep 2

To a 0.5M tetrahydrofuran solution of 1-propynylmagnesium bromide (800mL) was added dropwise a solution of5-(4-hydroxybenzylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dion e (47.3 g)obtained in Substep 1 in tetrahydrofuran (650 mL) under argon atmosphereat 11° C. over 40 minutes, followed by stirring the reaction mixture atroom temperature for 1 hour. Then, to the reaction mixture were addedsuccessively aqueous ammonium chloride solution (34 g/1 L) and hexane (1L), followed by removing the organic layer. After adding saturatedaqueous potassium hydrogen sulfate solution to the aqueous layer andadjusting a pH to 1, the aqueous layer was extracted with ethyl acetatetwice. The organic layer was dried and concentrated to give5-[1-(4-hydroxyphenyl)-but-2-ynyl]-2,2-dimethyl-[1,3]dioxan e-4,6-dione(54.8 g).

¹H-NMR (DMSO-d₆) δ: 1.60 (3H, s), 1.77 (3H, s), 1.81 (3H, d, J=2.6 Hz),4.60 (1H, t, J=2.4 Hz), 4.83 (1H, d, J=2.8 Hz), 6.67 (2H, d, J=8.6 Hz),7.30 (2H, d, J=8.6 Hz), 9.30 (1H, s).

Substep 3

To a suspension of5-[1-(4-hydroxyphenyl)-but-2-ynyl]-2,2-dimethyl-[1,3]dioxan e-4,6-dione(54.8 g) obtained in Substep 2 in 3-pentanone (200 mL) was added water(100 mL), followed by stirring the reaction mixture at 100° C. for 2days. After cooling down to room temperature, the aqueous layer of thereaction mixture was saturated with sodium chloride, followed byextraction with 3-pentanone. The organic layer was dried andconcentrated, followed by recrystallizing the residue from an ethylacetate-hexane mixed solvent to give 3-(4-hydroxyphenyl)-hex-4-ynoicacid (34.2 g).

¹H-NMR (DMSO-d₆) δ: 1.76 (3H, brs), 2.55 (2H, d, J=7.7 Hz), 3.87 (1H, t,J=7.7 Hz), 6.68 (2H, dd, J=8.6, 1.4 Hz), 7.13 (2H, dd, J=8.6, 1.2 Hz),9.28 (1H, s), 12.20 (1H, s).

Substep 4

To a solution of 3-(4-hydroxyphenyl)-hex-4-ynoic acid (34.2 g) obtainedin the same manner as in Substep 3 in 2-propanol (560 mL) was added asolution of (1S,2R)-1-amino-2-indanol (26.1 g) in 2-propanol (560 mL) at70° C. After this mixture was stirred at room temperature for 20 hours,the resulting crystal was filtered and heat-dissolved in 2-propanol (1.1L). After this mixture was further stirred at room temperature for 15hours, the resulting crystal was filtered and heat-dissolved in2-propanol (800 mL). After this mixture was stirred at room temperaturefor 18 hours, the resulting crystal was filtered and suspended in ethylacetate(150 mL)-water(60 mL). To the suspension was added aqueouspotassium hydrogen sulfate solution with vigorous stirring until thesuspension became a solution. The reaction mixture was extracted withethyl acetate twice. The organic layer was washed with saturated brine,dried and concentrated to give (S)-3-(4-hydroxyphenyl)-hex-4-ynoic acid(10.9 g, 99.4% ee). The optical purity was determined by chiral HPLCanalysis (column: DaicelChiralpakAD-RH, mobile phase: 15 v/v % aqueousacetonitrile solution containing 0.01% trifluoroacetic acid).

Substep 5

To a solution of (S)-3-(4-hydroxyphenyl)-hex-4-ynoic acid (10.9 g)obtained in Substep 4 in a mixed solvent of toluene (100 mL)-methanol(33 mL) was added dropwise a hexane solution oftrimethylsilyldiazomethane (2M, 32 mL) under ice-cooling for 10 minutes,followed by stirring at room temperature for 1 hour. Then, to thereaction mixture was added acetic acid (0.93 mL), followed byconcentration. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:3 to 1:2) to give(S)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester (10.6 g).

¹H-NMR (CDCl₃) δ: 1.84 (3H, d, J=2.6 Hz), 2.66 (1H, dd, J=15.2, 7.1 Hz),2.77 (1H, dd, J=15.3, 8.3 Hz), 3.67 (3H, s), 4.03-4.09 (1H, m), 4.80(1H, s), 6.78 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz).

Example 2 Preparation of(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt

To a solution of the compound (0.77 g) obtained in Example 1 in ethanol(7 mL) was added 4N aqueous sodium hydroxide solution (0.5 mL), followedby stirring at room temperature for 30 minutes. The reaction mixture wasconcentrated, and after addition of ethanol to the residue, the reactionmixture was further concentrated by azeotropic distillation twice(hereinafter abbreviated as “distilled azeotropically with ethanol”).The residue was dried in vacuo to give(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt (0.73 g) as the desired compound.

Example 3 Preparation of(S)-3-[4-(spiro[5.6]dodec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic noicacid Step 1

In the same manner as in Steps 1 to 7 of Example 1,spiro[5.6]dodec-2-en-2-yl-methanol was obtained fromcycloheptanecarbaldehyde.

¹H-NMR (CDCl₃) δ: 1.65-1.20 (14H, m), 1.78-1.80 (2H, m), 2.00-2.06 (2H,m), 3.98 (2H, s), 5.65-5.68 (1H, m).

Step 2

In the same manner as in Steps 8 to 9 of Example 1, the desired(S)-3-[4-(spiro[5.6]dodec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid wasobtained from the compound obtained in the above Step 1.

Example 4 Preparation of(S)-3-[4-(spiro[5.6]dodec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt

In the same manner as in Example 2, the desired compound was obtainedfrom the compound obtained in Example 3.

Example 5 Preparation of(S)-3-[4-(spiro[4.5]dec-7-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid Step1

In the same manner as in Steps 1 to 7 of Example 1,spiro[4.5]dec-7-en-7-yl-methanol was obtained fromcyclopentanecarbaldehyde.

¹H-NMR (CDCl₃) δ: 1.22 (1H, brs), 1.37-1.42 (4H, m), 1.46 (2H, t, J=6.4Hz), 1.61-1.68 (4H, m), 1.89-1.92 (2H, m), 2.06-2.12 (2H, m), 3.98 (2H,s), 5.64-5.68 (1H, m).

Step 2

In the same manner as in Steps 8 to 9 of Example 1, the desired compoundwas obtained from the compound obtained in the above Step 1.

Example 6 Preparation of(S)-3-[4-(spiro[4.5]dec-7-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt

In the same manner as in Example 2, the desired compound was obtainedfrom the compound obtained in the same manner as in Example 5.

Example 7 Preparation of(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

To a suspension of potassium tert-butoxide (22.4 g) in toluene (120 mL)was added a solution of cyclohexanone (9.82 g) and 1,4-dibromobutane(21.6 g) in toluene (30 mL) while stirring, followed by stirring thereaction mixture at 95° C. for 3.5 hours. After cooling down to roomtemperature and adding ice-cold water (100 mL) and 2N aqueoushydrochloric acid solution (50 mL) to the reaction mixture, the organiclayer was separated. Then, after the aqueous layer was extracted withethyl acetate, the organic layers were combined, washed with saturatedbrine, dried and concentrated. The residue was distilled in vacuo (90 to100° C./3 to 4 mmHg) to give spiro[4.5]decan-6-one (7.85 g).

¹H-NMR (CDCl₃) δ: 1.36-1.43 (2H, m), 1.54-1.63 (4H, m), 1.69-1.74 (4H,m), 1.79-1.86 (2H, m), 2.01-2.09 (2H, m), 2.38-2.42 (2H, m).

Step 2

To a suspension of 60% sodium hydride (4.59 g) and potassiumtert-butoxide (1.52 g) in tetrahydrofuran (100 mL) was added dimethylcarbonate (7.89 mL) under argon atmosphere at 85° C. To this mixture wasadded dropwise a solution of spiro[4.5]decan-6-one (8.74 g) obtained inthe same manner as in Step 1 in tetrahydrofuran (70 mL) over 1.5 hours.The reaction mixture was heated under reflux for 3 hours. Afterice-cooling, to the reaction mixture were added successively acetic acid(7.3 mL), water (85 mL) and ethyl acetate (175 mL), followed byseparation of the organic layer. The organic layer was washed withsaturated brine, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane (volumeratio)=1:100 to 1:90) to give 6-oxo-spiro[4.5]decane-7-carboxylic acidmethyl ester (9.99 g).

¹H-NMR (CDCl₃) δ: 1.07-1.18 (0.5H, m), 1.39-1.50 (1.5H, m), 1.53-1.87(8.5H, m), 1.98-2.29 (3H, m), 2.37-2.44 (0.5H, m), 3.57 (0.5H, dd,J=12.2, 6.2 Hz), 3.74 (1.5H, s), 3.74 (1.5H, s), 12.41 (0.5H, s).

Step 3

To a solution of 6-oxo-spiro[4.5]decane-7-carboxylic acid methyl ester(9.99 g) obtained in Step 2 in methanol (200 mL) was added platinumoxide (0.2 g) in an atmosphere of hydrogen (<0.3 Mpa) at roomtemperature overnight. Then, the reaction mixture was filtered throughCelite and the filtrate was concentrated. After adding ethyl acetate (30mL) and n-hexane (30 mL) to the residue, the resulting insolubles werefiltered off. The filtrate was concentrated and then dried in vacuo togive 6-hydroxy-spiro[4.5]decane-7-carboxylic acid methyl ester (10.11g).

¹H-NMR (CDCl₃) δ: 1.18-2.12 (13H, m), 2.31-2.56 (2H, m), 2.86 (1H, d,J=2.3 Hz), 3.64-3.75 (4H, m).

Step 4

To a solution of 6-hydroxy-spiro[4.5]decane-7-carboxylic acid methylester (10.1 g) obtained in Step 3 and triethylamine (19.9 mL) inchloroform (100 mL) was added dropwise methanesulfonyl chloride (5.2 mL)under ice-cooling, followed by stirring the reaction mixture at roomtemperature for 2 hours. Then, after addition of triethylamine (10 mL),the reaction mixture was stirred at room temperature for 30 minutes.After ice-cooling, ice-cold water (30 mL) and saturated aqueous sodiumbicarbonate solution (50 mL) were added to the reaction mixture,followed by separation of the organic layer. The organic layer waswashed with saturated brine, dried and concentrated to give a crude6-methanesulfonyloxy-spiro[4.5]decane-7-carboxylic acid methyl ester (22g).

Step 5

To a solution of the crude6-methanesulfonyloxy-spiro[4.5]decane-7-carboxylic acid methyl ester (22g) obtained in Step 4 in tetrahydrofuran (135 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (13.8 mL), followed by stirring thereaction mixture at 60° C. for 1.5 hours. After ice-cooling and adding1N aqueous hydrochloric acid solution (102 mL), the reaction mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane (volumeratio)=3:97 to 25:75) to give spiro[4.5]dec-6-ene-7-carboxylic acidmethyl ester (5.485 g).

¹H-NMR (CDCl₃) δ: 1.44-1.75 (12H, m), 2.22 (2H, ddd, J=6.3, 6.3, 1.9Hz), 3.72 (3H, s), 6.76 (1H, brs).

Step 6

To a solution of spiro[4.5]dec-6-ene-7-carboxylic acid methyl ester(3.50 g) obtained in Step 5 in tetrahydrofuran (70 mL) was addeddropwise a 1M toluene solution of diisobutylaluminum hydride (54.6 mL)under argon atmosphere at −70° C. over 15 minutes, followed by stirringthe reaction mixture at −70° C. for 2 hours. After raising thetemperature up to −15° C., to the reaction mixture were addedsuccessively 2N aqueous hydrochloric acid solution (60 mL) and ethylacetate (100 mL), followed by separation of the organic layer. Theorganic layer was washed with saturated brine, dried and concentrated.The residue was purified by column chromatography on silica gel (ethylacetate:hexane (volume ratio)=3:97 to 15:85) to givespiro[4.5]dec-6-ene-7-methanol (2.375 g).

¹H-NMR (CDCl₃) δ: 1.25-1.30 (1H, m), 1.42-1.47 (6H, m), 1.60-1.69 (6H,m), 1.97 (2H, brdd, J=6.3, 6.3 Hz), 3.98 (2H, s), 5.46 (1H, s).

Step 7

To a solution of spiro[4.5]dec-6-ene-7-methanol (1.0 g) obtained in Step6, (S)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester (1.77 g)obtained in the same manner as in Substep of Example 1 andtriphenylphosphine (2.64 g) in tetrahydrofuran (14 mL) was added1,1′-(azodicarbonyl)dipiperidine (2.26 g) under ice-cooling, followed bystirring at room temperature for 1.5 hours. After the reaction mixturewas concentrated, toluene (15 mL) and hexane (45 mL) were added to theresidue, followed by stirring at room temperature for 10 minutes. Theresulting insolubles were filtered off and the filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio))=4:96 to 8:92) to give(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (2.085 g).

¹H-NMR (CDCl₃) δ: 1.45-1.48 (6H, m), 1.62-1.69 (6H, m), 1.82 (3H, d,J=2.4 Hz), 2.03 (2H, brdd, J=6.3, 6.3 Hz), 2.65 (1H, dd, J=15.2, 7.0Hz), 2.75 (1H, dd, J=15.2, 8.2 Hz), 3.66 (3H, s), 4.02-4.08 (1H, m),4.33 (2H, s), 5.58 (1H, s), 6.84-6.88 (2H, m), 7.24-7.27 (2H, m).

Step 8

To a solution of(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (1.33 g) obtained in Step 7 in a mixed solvent oftetrahydrofuran (13 mL)-methanol (13 mL) was added 2N aqueous sodiumhydroxide solution (4.6 mL), followed by stirring the reaction mixtureat room temperature overnight. Then, to the reaction mixture were addedsuccessively 2N aqueous hydrochloric acid solution (5.1 mL), ethylacetate (100 mL) and sodium sulfate (50 g), followed by stirring for 30minutes. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=20:80) to give(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (895mg) as the desired compound.

Example 8 Preparation of(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt

To a solution of(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (1.12g) obtained in the same manner as in Example 7 in ethanol (30 mL) wasadded 1N aqueous sodium hydroxide solution (2.97 mL), followed bystirring the reaction mixture at room temperature for 1.5 hours. Thereaction mixture was concentrated and the residue was distilledazeotropically with ethanol twice. The residue was dried in vacuo at 60°C. for one day to give(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt (1.15 g) as the desired compound.

Example 9 Preparation of(S)-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidStep 1

In the same manner as in Steps 1 to 6 of Example 7,spiro[5.5]undec-1-en-2-yl-methanol was obtained from cyclohexanone and1,5-dibromopentane.

¹H-NMR (CDCl₃) δ: 1.24-1.53 (12H, m), 1.55-1.57 (1H, m), 1.62 (2H, tt,J=9.2, 3.1 Hz), 1.97 (2H, t, J=6.2 Hz), 3.99 (2H, d, J=6.0 Hz), 5.55(1H, s).

Step 2

In the same manner as in Steps 7 to 8 of Example 7, the desired compoundwas obtained from the compound obtained in the above Step 1.

Example 10 Preparation of(S)-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt

In the same manner as in Example 8, the desired compound was obtainedfrom the compound obtained in the same manner as in Example 9.

Example 11 Preparation of(S)-3-[4-(spiro[4.4]non-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

To a solution of potassium permanganate (55.3 g) in 1N aqueous sodiumhydroxide solution (300 mL) was added spiro[4.5]decan-8-one (10.6 g)obtained from cyclopentanecarbaldehyde in the same manner as in Steps 1and 2 of Example 1, followed by stirring the reaction mixture at roomtemperature for 3 hours. Then, to the reaction mixture was added aqueoussodium sulfite solution, followed by stirring the reaction mixture atroom temperature for 15 minutes. The insolubles in the reaction mixturewere filtered off and the filtrate was washed with diethyl ether. Theresulting aqueous solution was acidified by addition of concentratedhydrochloric acid thereto and extracted with ethyl acetate. The organiclayer was washed with water, dried and concentrated to give a crudeproduct (12.75 g) containing 3-(1-carboxymethyl-cyclopentyl)-propionicacid.

Step 2

To a solution of the crude product (12.75 g) containing3-(1-carboxymethyl-cyclopentyl)-propionic acid obtained in Step 1 in amixed solvent of acetonitrile (150 mL)-N,N-dimethylformamide (50 mL)were added successively benzyl bromide (18.3 mL) and cesium carbonate(57 g) at 50° C., followed by stirring at 50° C. for 2 hours. Then,after addition of benzyl bromide (9 mL) and cesium carbonate (30 g), thereaction mixture was heated at 60° C. for 45 minutes. After cooling downto room temperature and adding ice-cold water to the reaction mixture,the reaction mixture was extracted with diethyl ether. The organic layerwas washed with water, dried and concentrated. The residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate (volumeratio)=10:1) to give a crude product (14.9 g) containing3-(1-benzyloxycarbonylmethyl-cyclopentyl)-propionic acid benzyl ester.

Step 3

To a solution of the crude product (14.9 g) containing3-(1-benzyloxycarbonylmethyl-cyclopentyl)-propionic acid benzyl esterobtained in Step 2 in tetrahydrofuran (150 mL) was added potassiumtert-butoxide (6.6 g), followed by stirring at room temperature for 2hours. Then, to the reaction mixture was added dropwise a solution ofacetic acid (5 mL) in water (100 mL) under ice-cooling, followed byextraction with ethyl acetate. The organic layer was washed with water,dried and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate (volume ratio)=20:1to 10:1) to give a crude product (5.23 g) containing3-oxo-spiro[4.4]nonane-2-carboxylic acid benzyl ester.

Step 4

To a solution of the crude product (5.23 g) containing3-oxo-spiro[4.4]nonane-2-carboxylic acid benzyl ester obtained in Step 3in methanol (100 mL) was added sodium borohydride (254 mg) underice-cooling, followed by stirring under ice-cooling for 30 minutes.Then, after addition of 10% aqueous potassium hydrogen sulfate solution(10 mL) to the reaction mixture, methanol was evaporated off in vacuo,followed by extraction with ethyl acetate. The organic layer was driedand concentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate (volume ratio)=10:1 to 3:1) to give3-hydroxy-spiro[4.4]nonane-2-carboxylic acid benzyl ester (less-polarisomer; 1.29 g, more-polar isomer; 2.23 g). Less-polar isomer

¹H-NMR (CDCl₃) δ: 1.45-1.66 (9H, m), 1.78 (1H, dd, J=13.1, 10.1 Hz),1.93-2.02 (2H, m), 2.13 (1H, d, J=3.8 Hz), 2.80-2.88 (1H, m), 4.46 (1H,dd, J=15.1, 7.4, 3.8 Hz), 5.17 (2H, s), 7.30-7.42 (5H, m).

More-polar isomer

¹H-NMR (CDCl₃) δ: 1.37-1.51 (2H, m), 1.68-1.52 (7H, m), 1.74 (1H, dd,J=14.1, 3.2 Hz), 1.82-1.91 (2H, m), 2.88-2.94 (2H, m), 4.45-4.51 (1H,m), 5.17 (2H, d, J=1.9 Hz), 7.29-7.42 (5H, m).

Step 5

3-Hydroxy-spiro[4.4]nonane-2-carboxylic acid benzyl ester (less-polarisomer; 1.29 g, more-polar isomer; 2.23 g) obtained in Step 4 wassubjected to the reaction in the same condition as in Steps 5, 5′ and 6of Example 1 to give spiro[4.4]non-2-ene-2-carboxylic acid benzyl ester(3.2 g).

¹H-NMR (CDCl₃) δ: 1.71-1.44 (8H, m), 2.42 (2H, q, J=2.5 Hz), 2.52 (2H,q, J=2.2 Hz), 5.18 (2H, s), 6.75-6.78 (1H, m), 7.29-7.39 (5H, m).

Step 6

Spiro[4.4]non-2-ene-2-carboxylic acid benzyl ester (3.2 g) obtained inStep 5 was subjected to the reaction in the same condition as in Step 7of Example 1 to give spiro[4.4]non-2-en-2-yl-methanol (1.8 g).

¹H-NMR (CDCl₃) δ: 1.58-1.54 (4H, m), 1.62-1.68 (4H, m), 2.25-2.30 (4H,m), 4.16 (2H, s), 5.53-5.57 (1H, m).

Step 7

Spiro[4.4]non-2-en-2-yl-methanol (0.8 g) obtained in Step 6 and(S)-3-(4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (1.6 g) obtainedin the same manner as in Substep 5 of Example 1 were subjected to thereaction in the same condition as in Step 8 of Example 1 to give(S)-3-[4-(spiro[4.4]non-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (1.55 g).

¹H-NMR (CDCl₃) δ: 1.59-1.56 (4H, m), 1.62-1.67 (4H, m), 1.84 (3H, d,J=2.5 Hz), 2.29-2.33 (4H, m), 2.66 (1H, dd, J=15.3, 6.8 Hz), 2.76 (1H,dd, J=15.3, 8.3 Hz), 3.67 (3H, s), 4.03-4.09 (1H, m), 4.52 (2H, s),5.64-5.68 (1H, m), 6.87 (2H, d, J=8.3 Hz), 7.27 (3H, d, J=8.3 Hz).

Step 8

(S)-3-[4-(spiro[4.4]non-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (1.55 g) obtained in step 7 was subjected to the reactionin the same condition as in Step 9 of Example 1 to give(S)-3-[4-(spiro[4.4]non-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid (1.37g) as the desired compound.

Example 12 Preparation of(S)-3-[4-(spiro[4.4]non-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt

In the same manner as in Example 2 or 4, the desired compound wasobtained from the compound obtained in Example 11.

Example 13 Preparation of(S)-3-[4-(spiro[4.5]dec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid Step1

In the same manner as in Steps 1 to 6 of Example 11,spiro[4.5]dec-2-en-2-yl-methanol was obtained fromcyclohexanecarbaldehyde.

¹H-NMR (CDCl₃) δ: 1.49-1.36 (10H, m), 2.14-2.19 (4H, m), 4.12-4.16 (2H,m), 5.47-5.50 (1H, m).

Step 2

In the same manner as in Steps 7 to 8 of Example 11, the desiredcompound was obtained from the compound obtained in the above Step 1.

Example 14 Preparation of(S)-3-[4-(spiro[4.5]dec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt

In the same manner as in Example 12, the desired compound was obtainedfrom the compound obtained in the same manner as in Example 13.

Example 15 Preparation of(S)-3-[4-(spiro[4.5]dec-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

To a solution of cyclohexanecarbaldehyde (6.3 mL) and2-hydroxy-3-butenoic acid methyl ester (5 mL) in toluene (40 mL) wasadded para-toluenesulfonic acid monohydrate (20 mg), and the reactionmixture was heated under reflux by using a Dean-Stark apparatus for 16.5hours. After cooling down to room temperature, the reaction mixture wasconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (hexane:ethyl acetate (volume ratio)=50:1 to 10:1) to give4-(1-formyl-cyclohexyl)-but-2-enoic acid methyl ester (3.7 g).

¹H-NMR (CDCl₃) δ: 1.30-1.42 (4H, m), 1.53-1.58 (4H, m), 1.85-1.91 (2H,m), 2.33 (2H, dd, J=7.7, 1.3 Hz), 3.72 (3H, s), 5.84 (1H, dt, J=15.7,1.3 Hz), 6.81 (1H, ddd, J=7.7, 15.7, 7.8 Hz), 9.48 (1H, s).

Step 2

To a solution of 4-(1-formyl-cyclohexyl)-but-2-enoic acid methyl ester(3.7 g) obtained in Step 1 and tris(triphenylphosphine)rhodium (I)chloride (163 mg) in toluene (80 mL) was added dropwise triethylsilane(5.9 mL) under argon atmosphere over 10 minutes, followed by stirringthe reaction mixture at 55° C. for 27 hours. After cooling down to roomtemperature and adding aqueous sodium bicarbonate solution, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith water, dried and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate (volume ratio)=20:1)to give 1-triethylsiloxy-spiro[4.5]decane-2-carboxylic acid methyl ester(5.0 g).

Step 3

To a solution of 1-triethylsiloxy-spiro[4.5]decane-2-carboxylic acidmethyl ester (5.0 g) obtained in Step 2 in tetrahydrofuran (30 mL) wasadded a 1M tetrahydrofuran solution of tetra-n-butylammonium fluoride(18.4 mL), followed by stirring the reaction mixture at room temperaturefor 30 minutes. Then, after addition of aqueous ammonium chloridesolution, the reaction mixture was extracted with ethyl acetate. Theorganic layer was washed with water, dried and concentrated. The residuewas purified by column chromatography on silica gel (hexane:ethylacetate (volume ratio)=5:1) to give1-hydroxy-spiro[4.5]decane-2-carboxylic acid methyl ester (less-polarisomer; 1.6 g, more-polar isomer; 0.95 g).

More-polar isomer

¹H-NMR (CDCl₃) δ: 1.17-1.53 (6H, m), 1.58-1.61 (4H, m), 1.76-1.85 (2H,m), 1.89-1.98 (1H, m), 2.02 (1H, d, J=4.5 Hz), 2.71-2.79 (1H, m), 3.72(3H, s), 3.77 (1H, dd, J=9.0, 4.2 Hz).

Step 4

1-Hydroxy-spiro[4.5]decane-2-carboxylic acid methyl ester obtained inStep 3 (more-polar isomer; 0.95 g) was subjected to the reaction in thesame condition as in Steps 5 and 6 of Example 1 to givespiro[4.5]dec-1-ene-2-carboxylic acid methyl ester (800 mg).

¹H-NMR (CDCl₃) δ: 1.39-1.52 (10H, brm), 1.77 (2H, t, J=7.4 Hz), 2.56(2H, td, J=7.4, 1.8 Hz), 3.73 (3H, s), 6.69 (1H, s).

Step 5

Spiro[4.5]dec-1-ene-2-carboxylic acid methyl ester (800 mg) obtained inStep 4 was subjected to the reaction in the same condition as in Step 7of Example 1 to give spiro[4.5]dec-1-en-2-yl-methanol (675 mg).

¹H-NMR (CDCl₃) δ: 1.33-1.50 (14H, brm), 1.73 (2H, t, J=7.0 Hz), 2.31(2H, t, J=7.0 Hz), 4.16 (2H, d, J=6.5 Hz), 5.56 (1H, s).

Step 6

To a solution of spiro[4.5]dec-1-en-2-yl-methanol (50 mg) obtained inStep 5 in chloroform (1 mL) were added triphenylphosphine (87 mg) andN-bromo-succinimide (87 mg) under ice-cooling, followed by stirring thereaction mixture at room temperature for 1 hour. Then, the reactionmixture was concentrated in vacuo and the residue was purified by columnchromatography on silica gel (hexane) to give2-bromomethyl-spiro[4.5]dec-1-ene (55 mg).

¹H-NMR (CDCl₃) δ: 1.36-1.51 (10H, brm), 1.75 (2H, t, J=7.4 Hz), 2.42(2H, t, J=7.4 Hz), 4.04 (2H, s), 5.71 (1H, s).

Step 7

To a solution of 2-bromomethyl-spiro[4.5]dec-1-ene (55 mg) obtained inStep 6 in N,N-dimethylformamide (1 mL) were added(S)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester (60 mg) obtainedin the same manner as in Substep 5 of Example 1 and potassium carbonate(93 mg), followed by stirring the reaction mixture at room temperaturefor 15 hours. Then, after addition of 1N aqueous hydrochloric acidsolution, the reaction mixture was extracted with diethyl ether. Theorganic layer was washed with water, dried and concentrated. The residuewas purified by column chromatography on silica gel (hexane:ethylacetate (volume ratio)=50:1 to 20:1) to give(S)-3-[4-(spiro[4.5]dec-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (71 mg).

¹H-NMR (CDCl₃) δ: 1.40-1.59 (10H, brm), 1.76 (2H, t, J=8.0 Hz), 1.84(3H, d, J=2.3 Hz), 2.39 (2H, t, J=8.0 Hz), 2.66 (1H, dd, J=15.3, 7.0Hz), 2.76 (1H, dd, J=15.3, 7.8 Hz), 3.67 (3H, s), 4.04-4.08 (1H, m),4.52 (2H, s), 5.68 (1H, s), 6.87 (2H, d, J=8.7 Hz), 7.27 (2H, d, J=8.7Hz).

Step 8

(S)-3-[4-(spiro[4.5]dec-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (71 mg) obtained in Step 7 was subjected to the reaction inthe same condition as in Step 9 of Example 1 to give(S)-3-[4-(spiro[4.5]dec-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid (57mg) as the desired compound.

Example 16 Preparation of(S)-3-[4-(spiro[4.5]dec-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt

In the same manner as in Example 2 or 4, the desired compound wasobtained from the compound obtained in Example 15.

Example 17 Preparation of(S)-3-[4-(spiro[4.4]non-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid Step1

In the same manner as in Steps 1 to 5 of Example 15,spiro[4.4]non-1-en-2-yl-methanol was obtained fromcyclopentanecarbaldehyde.

¹H-NMR (CDCl₃) δ: 1.56-1.47 (4H, m), 1.69-1.63 (4H, m), 1.80 (3H, t,J=7.2 Hz), 2.33 (2H, t, J=7.2 Hz), 4.18 (2H, d, J=4.6 Hz), 5.48 (1H, s).

Step 2

In the same manner as in Steps 6 to 8 of Example 15, the desiredcompound was obtained from the compound obtained in the above Step 1.

Example 18 Preparation of(S)-3-[4-(spiro[4.4]non-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt

In the same manner as in Example 16, the desired compound was obtainedfrom the compound obtained in Example 17.

Example 19 Preparation of(3S)-3-[4-(11,11-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)-phenyl]-hex-4-ynoicacid

Step 1

To a solution of 4,4-dimethyl-cyclohexane-1,3-dione (6.0 g) in methanol(80 mL) was added para-toluenesulfonic acid monohydrate (813 mg),followed by heating the reaction mixture under reflux for 2 hours. Aftercooling down to room temperature, the reaction mixture was concentrated.The residue was purified by column chromatography on silica gel(hexane:ethyl acetate (volume ratio)=3:1) to give a less-polar isomer(3.7 g) and a more-polar isomer (1.1 g).

Less-polar isomer

¹H-NMR (CDCl₃) δ: 1.12 (6H, s), 1.81 (2H, t, J=6.3 Hz), 2.44 (2H, t,J=6.3 Hz), 3.69 (3H, s), 5.27 (1H, s).

More-polar isomer

¹H-NMR (CDCl₃) δ: 1.20 (6H, s), 1.83 (2H, t, J=6.7 Hz), 2.41 (2H, t,J=6.7 Hz), 3.68 (3H, s), 5.26 (1H, s).

Step 2

To magnesium (237 mg) was added dropwise a solution of 5-bromo-1-pentene(1.15 mL) in tetrahydrofuran (15 mL) under argon atmosphere over 20minutes, followed by stirring the reaction mixture at room temperaturefor 30 minutes. To the reaction mixture was added dropwise a solution ofthe less-polar isomer (1.0 g) obtained in Step 1 in tetrahydrofuran (10mL) under ice-cooling, followed by stirring the reaction mixture at roomtemperature overnight. Then, after addition of 12% aqueous hydrochloricacid solution (10 mL) under ice-cooling, the reaction mixture wasextracted with diethyl ether. The organic layer was washed with water,dried and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate (volume ratio)=10:1)to give 4,4-dimethyl-3-pent-4-enyl-cyclohex-2-enone (1.07 g).

¹H-NMR (CDCl₃) δ: 1.17 (6H, s), 1.61 (2H, tt, J=7.5, 7.5 Hz), 1.86 (2H,t, J=6.8 Hz), 2.12 (2H, q, J=7.5 Hz), 2.22 (2H, t, J=7.5 Hz), 2.45 (2H,t, J=6.8 Hz), 4.95-5.08 (2H, m), 5.75-5.87 (2H, m).

Step 3

To a suspension of lithium aluminum hydride (250 mg) in diethyl ether(20 mL) was added dropwise a solution of4,4-dimethyl-3-pent-4-enyl-cyclohex-2-enone (1.05 g) obtained in Step 2in diethyl ether (5 mL) under ice-cooling and nitrogen atmosphere,followed by stirring the reaction mixture under ice-cooling for 30minutes. Then, after successive dropwise addition of water (0.25 mL), 4Naqueous sodium hydroxide solution (0.25 mL) and water (0.75 mL), thereaction mixture was stirred at room temperature for 30 minutes. Afterthe resulting insolubles were filtered off, the filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate (volume ratio)=15:1 to 10:1) to give4,4-dimethyl-3-pent-4-enyl-cyclohex-2-enol (830 mg).

¹H-NMR (CDCl₃) δ: 0.98 (3H, s), 1.04 (3H, s), 1.32-1.65 (5H, m),1.83-1.92 (1H, m), 1.92-2.02 (2H, m), 2.08 (2H, q, J=7.3 Hz), 4.12-4.21(1H, m), 4.93-5.06 (2H, m), 5.37-5.41 (1H, m), 5.75-5.90 (1H, m).

Step 4

To 4,4-dimethyl-3-pent-4-enyl-cyclohex-2-enol (810 mg) obtained in Step3 was added formic acid (60 mL), followed by stirring the reactionmixture at room temperature for 2 hours and then at 50° C. for 3 hours.After cooling down to room temperature and adding water, the reactionmixture was extracted with chloroform. The organic layer was washed withwater, dried and concentrated. The residue was reduced in the samecondition as in Step 3 to give 11,11-dimethyl-spiro[5.5]undec-7-en-2-ol(340 mg).

¹H-NMR (CDCl₃) δ: 0.86 (3H, s), 0.89 (3H, s), 1.11 (1H, dq, J=4.6, 11.6Hz), 1.21-1.44 (4H, m), 1.49-1.71 (3H, m), 1.79 (1H, dq, J=11.6, 2.1 Hz),1.98-2.03 (3H, m), 3.82-3.89 (1H, m), 5.57-5.63 (1H, m), 5.71 (1H, dd,J=10.3, 2.0 Hz).

Step 5

To a solution of 11,11-dimethyl-spiro[5.5]undec-7-en-2-ol (320 mg)obtained in Step 4 in chloroform (10 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Dess-Martin periodinane; 735 mg) under ice-cooling, followed bystirring the reaction mixture under ice-cooling for 3 hours. Then, afteraddition of aqueous sodium sulfite solution to the reaction mixture,chloroform was evaporated off in vacuo. To the residue was added aqueoussodium bicarbonate solution, followed by extraction with ethyl acetate.The organic layer was washed with water, dried and concentrated. Theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate (volume ratio)=20:1) to give11,11-dimethyl-spiro[5.5]undec-7-en-2-one (290 mg).

Step 6

To a solution of 11,11-dimethyl-spiro[5.5]undec-7-en-2-one (290 mg)obtained in Step 5 and dimethyl(1-diazo-2-oxopropyl)-phosphonate (435mg) obtained in the following Substep in methanol (6 mL) was addedpotassium carbonate (420 mg) under ice-cooling, followed by stirring thereaction mixture at room temperature overnight. Then, after addition ofaqueous ammonium chloride solution, the reaction mixture was extractedwith diethyl ether. The organic layer was washed with water, dried andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate (volume ratio)=15:1) to give8-(1-methoxymethylidene)-5,5-dimethyl-spiro[5.5]undec-1-ene (240 mg).

Step 7

To a solution of8-(1-methoxymethylidene)-5,5-dimethyl-spiro[5.5]undec-1-ene (240 mg)obtained in Step 6 in acetonitrile (6 mL) was added 1N aqueoushydrochloric acid solution (1.1 mL), followed by stirring the reactionmixture at room temperature for 3 hours. Then, after addition ofsaturated brine, the reaction mixture was extracted with diethyl ether.The organic layer was washed with water, dried and concentrated. Theresulting residue was dissolved in a mixed solution of methanol (5.4mL)-water (0.6 mL). To the solution was added potassium carbonate (150mg), followed by stirring the reaction mixture at room temperature for 2hours. Then, after addition of water, the reaction mixture was extractedwith diethyl ether. The organic layer was washed with water, dried andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate (volume ratio)=40:1) to give11,11-dimethyl-spiro[5.5]undec-7-ene-2-carbaldehyde (195 mg).

¹H-NMR (CDCl₃) δ: 0.91-0.86 (6H, m), 1.08-1.79 (9H, m), 1.94-2.06 (3H,m), 2.45-2.56 (1H, m), 5.62-5.70 (1H, m), 5.76-5.83 (1H, m), 9.59-9.63(1H, m).

Step 8

To a solution of 11,11-dimethyl-spiro[5.5]undec-7-ene-2-carbaldehyde(195 mg) obtained in Step 7 in methanol (5 mL) was added sodiumborohydride (55 mg) underice-cooling, followed by stirring the reactionmixture under ice-cooling for 15 minutes. Then, after addition of 0.5Naqueous sodium hydroxide solution (10 mL), the reaction mixture wasextracted with diethyl ether. The organic layer was washed with water,dried and concentrated. The residue was purified by columnchromatography on silica gel (hexane:ethyl acetate (volume ratio)=10:1to 5:1) to give (11,11-dimethyl-spiro[5.5]undec-7-en-2-yl)-methanol (190mg).

¹H-NMR (CDCl₃) δ: 0.85 (6H, d, J=2.3 Hz), 1.04 (1H, t, J=12.2 Hz),1.17-1.85 (10H, m), 1.95-2.02 (2H, m), 3.40-3.47 (2H, m), 5.59 (1H, dt,J=10.2, 3.0 Hz), 5.85 (1H, dt, J=10.2, 2.3 Hz).

Step 9

(11,11-Dimethyl-spiro[5.5]undec-7-en-2-yl)-methanol (67 mg) obtained inStep 8 and (S)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester (77 mg)obtained in the same manner as in Substep 5 of Example 1 were subjectedto the reaction in the same condition as in Step 8 of Example 1 to give(3S)-3-[4-(11,11-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (119 mg).

¹H-NMR (CDCl₃) δ: 0.87 (6H, s), 0.90-0.96 (1H, m), 1.15 (1H, t, J=12.4Hz), 1.68-1.33 (7H, m), 1.83 (3H, d, J=2.3 Hz), 1.93 (1H, d, J=12.5 Hz),1.98-2.12 (3H, m), 2.66 (1H, dd, J=15.3, 7.0 Hz), 2.76 (1H, dd, J=15.3,8.3 Hz), 3.67 (3H, s), 3.69-3.76 (2H, m), 4.03-4.09 (1H, m), 5.62 (1H,td, J=3.0, 10.2 Hz), 5.89 (1H, dt, J=10.2, 2.0 Hz), 6.84 (2H, d, J=9.4Hz), 7.27 (2H, d, J=9.4 Hz).

Step 10

(3S)-3-[4-(11,11-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (119 mg) obtained in Step 9 was subjected to thereaction in the same condition as in Step 9 of Example 1 to give(3S)-3-[4-(11,11-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)-phenyl]-hex-4-ynoicacid (104 mg) as the desired compound.

Substep

Toa suspension of 60% sodium hydride (2.5 in toluene (100mL)-tetrahydrofuran (40 mL) was added dropwise a solution of dimethyl2-oxopropyl phosphonate (10 in tetrahydrofuran (40 mL) under ice-coolingand nitrogen atmosphere over 10 minutes, followed by stirring thereaction mixture under ice-cooling for 1 hour. Then, to the reactionmixture was added dropwise a solution of para-dodecylbenzenesulfonylazide (22 g) in tetrahydrofuran (40 mL) over 10 minutes, followed bystirring in the range of ice-cooling to room temperature for 3 hours.Then, the reaction mixture was concentrated in vacuo and the resultingresidue was purified by column chromatography on silica gel(hexane:ethyl acetate (volume ratio)=1:1) to givedimethyl(1-diazo-2-oxo-propyl)-phosphonate (4.2 g).

Example 20 Preparation of(3S)-3-[4-(11,11-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)-phenyl]-hex-4-ynoicacid sodium salt

In the same manner as in Example 2 or 4, the desired compound wasobtained from the compound obtained in Example 19.

Example 21 Preparation of3-[4-(spiro[4.6]undec-2-ylmethoxy)phenyl]-propionic acid

Step 1

To a solution of 3-ethoxycyclopent-2-enone (2.37 g) in tetrahydrofuran(30 mL) was added dropwise a 0.5M tetrahydrofuran solution of3-butenylmagnesium bromide (38.4 mL) under nitrogen atmosphere at −78°C. over 10 minutes, followed by stirring at −78° C. for 3 hours and thenat room temperature overnight. Then, after addition of 2N aqueoushydrochloric acid solution, the reaction mixture was stirred for 30minutes and then extracted with ethyl acetate twice. The organic layerwas washed with saturated brine, dried and concentrated. The residue waspurified by column chromatography on silica gel to give3-(3-butenyl)cyclopent-2-enone (1.1 g).

¹H-NMR (CDCl₃) δ: 2.37 (4H, dtd, J=17.90, 5.65, 2.95 Hz), 2.50-2.61 (4H,m), 5.04-5.09 (2H, m), 5.75-5.89 (1H, m), 5.98 (1H, s).

Step 2

To a suspension of copper(I) iodide (2.6 g) and lithium bromide (1.2 g)in tetrahydrofuran (25 mL) was added dropwise a 0.5M tetrahydrofuransolution of 3-butenylmagnesium bromide (26.5 mL) under nitrogenatmosphere at −78° C. over 6 minutes, followed by stirring the reactionmixture at −78° C. for 40 minutes. Then, 5 minutes after addition ofboron trifluoride diethyl ether complex (0.554 mL), to the reactionmixture was added 3-(3-butenyl)cyclopent-2-enone (0.6 g) obtained inStep 1. Half an hour later, after addition of boron trifluoride diethylether complex (0.250 mL), the reaction mixture was stirred at −78° C.for 2 hours, and further stirred at room temperature overnight afterremoving a dry-ice/ethanol bath. Then, after addition of saturatedaqueous ammonium chloride solution and 28% aqueous ammonia solution, thereaction mixture was extracted with ethyl acetate. The organic layer waswashed successively with aqueous ammonia solution and saturated brine,dried and concentrated. The residue was purified by columnchromatography on silica gel to give 3,3-dibut-3-enylcyclopentanone (380mg).

¹H-NMR (CDCl₃) δ: 1.48-1.57 (4H, m), 1.84 (2H, t, J=8.0 Hz), 1.95-2.09(4H, m), 2.11 (2H, s), 2.28 (2H, t, J=8.0 Hz), 4.95-5.08 (4H, m),5.79-5.85 (2H, m).

Step 3

A solution of 3,3-dibut-3-enylcyclopentanone (380 mg) obtained in Step 2in toluene (80 mL) was degassed with argon. After addition ofbenzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (84 mg), the reaction mixture was heated under reflux for 6hours. After cooling down to room temperature, the reaction mixture wasconcentrated. The residue was purified by column chromatography onsilica gel to give spiro[4.6]undec-8-en-2-one (350 mg).

Step 4

To a solution of spiro[4.6]undec-8-en-2-one (350 mg) obtained in Step 3and dimethyl(1-diazo-2-oxo-propyl)-phosphonate (768 mg) obtained in thesame manner as in Substep of Example 19 in methanol (10 mL) was addedpotassium carbonate (830 mg) under ice-cooling, followed by stirring thereaction mixture under ice-cooling for 2.5 hours. Then, the reactionmixture was poured into water, followed by extraction with ethylacetate. The organic layer was washed successively with water andsaturated brine, dried and concentrated to give2-(1-methoxymethylidene)spiro[4.6]undec-8-ene (900 mg) as a crudeproduct.

Step 5

To a solution of the crude 2-(1-methoxymethylidene)spiro[4.6]undec-8-ene(900 mg) obtained in Step 4 in acetonitrile (10 mL) was added 1N aqueoushydrochloric acid solution (2 mL), followed by stirring at roomtemperature for 4 hours. Then, the reaction mixture was poured intowater, followed by extraction with ethyl acetate. The organic layer waswashed with saturated brine, dried and concentrated. The residue waspurified by column chromatography on silica gel to givespiro[4.6]undec-8-ene-2-carbaldehyde (44 mg).

Step 6

To a solution of spiro[4.6]undec-8-ene-2-carbaldehyde (44 mg) obtainedin Step 5 in methanol (1 mL) was added sodium borohydride (9 mg),followed by stirring at room temperature overnight. Then, after additionof aqueous hydrochloric acid solution, the reaction mixture wasextracted with ethyl acetate twice. The organic layer was washed withsaturated brine, dried and concentrated to givespiro[4.6]undec-8-ene-2-methanol (44 mg).

Step 7

A suspension of spiro[4.6]undec-8-ene-2-methanol (44 mg) obtained inStep 6 and 5% palladium carbon (4 mg) in tetrahydrofuran (1 mL)-ethanol(1 mL) was stirred in an atmosphere of hydrogen for 3 hours. Then, thereaction mixture was filtered through Celite and the filtrate wasconcentrated. The residue was purified by column chromatography onsilica gel to give spiro[4.6]undecane-2-methanol (43 mg).

¹H-NMR (CDCl₃) δ: 0.98 (1H, dd, J=12.43, 9.42 Hz), 1.24-1.36 (3H, m),1.44-1.53 (12H, m), 1.69 (1H, dd, J=12.40, 7.72 Hz), 1.74-1.83 (1H, m),2.12-2.22 (1H, m), 3.53 (2H, d, J=5.27 Hz).

Step 8

To a solution of spiro[4.6]undecane-2-methanol (43 mg) obtained in Step7, 3-(4-hydroxyphenyl) propionic acid methyl ester (51 mg) andtriphenylphosphine (74 mg) in tetrahydrofuran (1 mL) was added1,1′-azobis(N,N-dimethylformamide) (49 mg) under ice-cooling, followedby stirring the reaction mixture at room temperature overnight. Thereaction mixture was concentrated and the residue was purified by columnchromatography on silica gel to give3-[4-(spiro[4.6]undec-2-ylmethoxy)-phenyl]-propionic acid methyl ester(75 mg).

¹H-NMR (CDCl₃) δ: 1.08 (1H, dd, J=12.6, 9.3 Hz), 1.41-1.49 (15H, m),1.77-1.85 (2H, m), 2.40-2.43 (1H, m), 2.59 (2H, t, J=7.7 Hz), 2.88 (2H,t, J=7.7 Hz), 3.66 (3H, s), 3.80 (2H, d, J=6.8 Hz), 6.81 (2H, d, J=8.7Hz), 7.09 (2H, d, J=8.7 Hz).

Step 9

To a solution of 3-[4-(spiro[4.6]undec-2-ylmethoxy)-phenyl]-propionicacid methyl ester (75 mg) obtained in Step 8 in a mixed solvent ofethanol (1 mL)-tetrahydrofuran (1 mL) was added 1N aqueous sodiumhydroxide solution (0.22 mL), followed by stirring the reaction mixtureat room temperature for 5 hours. Then, after concentrating the reactionmixture, to the residue was added dropwise 2N aqueous hydrochloric acidsolution. The precipitate was filtered, washed with water and dried invacuo to give 3-[4-(spiro[4.6]undec-2-ylmethoxy)-phenyl]-propionic acid(70.6 mg) as the desired compound.

Example 22 Preparation of

(S)-3-[4-(spiro[4.5]dec-8-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

To a solution of spiro[4.5]decan-8-one (4.2 g) produced fromcyclopentanecarbaldehyde in the same manner as in Steps 1 and 2 ofExample 1 in tetrahydrofuran (30 mL) were added successivelytrimethylsilyl cyanide (2.9 mL) and a tetrahydrofuran solution oftetra-n-butylammonium fluoride (1M, 22 mL), followed by stirring thereaction mixture at room temperature for 4 hours. Then, after additionof saturated aqueous sodium bicarbonate solution, the reaction mixturewas extracted with ethyl acetate twice. The organic layer was washedwith saturated brine, dried and concentrated to give8-hydroxy-spiro[4.5]decane-8-carbonitrile (3.9 g).

¹H-NMR (CDCl₃) δ: 1.41-1.47 (4H, m), 1.54-1.65 (8H, m), 1.76-1.80 (4H,m).

Step 2

To a solution of 8-hydroxy-spiro[4.5]decane-8-carbonitrile (3.9 g)obtained in Step 1 in tetrahydrofuran (30 mL) were added successivelypyridine (4.4 mL) and thionyl chloride (1.8 mL), followed by stirringthe reaction mixture at room temperature for 15 hours. Then, afteraddition of 1N aqueous hydrochloric acid solution, the reaction mixturewas extracted with diethyl ether. The organic layer was washedsuccessively with 1N aqueous hydrochloric acid solution and saturatedbrine, dried and concentrated to give spiro[4.5]dec-7-ene-8-carbonitrile(2.8 g).

¹H-NMR (CDCl₃) δ: 1.35-1.44 (4H, m), 1.54 (2H, t, J=6.4 Hz), 1.62-1.67(4H, m), 2.06 (2H, dd, J=6.4, 2.4 Hz), 2.24-2.30 (2H, m), 6.55-6.59 (1H,m).

Step 3

To a solution of spiro[4.5]dec-7-ene-8-carbonitrile (2.8 g) obtained inStep 2 in ethanol (30 mL) was added concentrated sulfuric acid (3 mL),followed by heating the reaction mixture under reflux while stirring for5 days. After cooling down to room temperature and adding water, thereaction mixture was extracted with ethyl acetate twice. The organiclayer was washed successively with saturated aqueous sodium bicarbonatesolution and saturated brine, dried and concentrated. The residue waspurified by column chromatography on silica gel (ethyl acetate:hexane(volume ratio)=1:4) to give spiro[4.5]dec-7-ene-8-carboxylic acid ethylester (2.8 g).

¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J=7.0 Hz), 1.36-1.42 (4H, m), 1.52 (2H,t, J=6.4 Hz), 1.61-1.66 (4H, m), 2.07 (2H, dd, J=6.4, 2.6 Hz), 2.29-2.31(2H, m), 4.18 (2H, q, J=7.0 Hz), 6.90-6.94 (1H, m).

Step 4

To a solution of spiro[4.5]dec-7-ene-8-carboxylic acid ethyl ester (2.8g) obtained in Step 3 in tetrahydrofuran (40 mL) was added dropwise atoluene solution of diisobutylaluminum hydride (0.99 M, 41 mL) underargon atmosphere at −78° C., followed by stirring the reaction mixtureat −78° C. for 1 hour. Then, after adding 2N aqueous hydrochloric acidsolution and raising the temperature to room temperature, the reactionmixture was extracted with ethyl acetate twice. The organic layer waswashed with saturated brine, dried and concentrated. The residue waspurified by column chromatography on silica gel (ethyl acetate:hexane(volume ratio)=1:4) to give spiro[4.5]dec-7-en-8-yl-methanol (1.95 g).

¹H-NMR (CDCl₃) δ: 1.37-1.41 (4H, m), 1.51 (2H, t, J=6.5 Hz), 1.59-1.65(4H, m), 1.90-1.93 (2H, m), 2.04-2.06 (2H, m), 4.00 (2H, s), 5.62 (1H,s).

Step 5

To a solution of spiro[4.5]dec-7-en-8-yl-methanol (0.7 g) obtained inStep 4 in a mixed solvent of tetrahydrofuran (7 mL)-methanol (7 mL) wasadded 5% palladium carbon (70 mg), followed by stirring the reactionmixture at room temperature under normal pressure in an atmosphere ofhydrogen for 1.5 hours and then under increased pressure of 0.3 MPa inan atmosphere of hydrogen for 3 hours. Then, the reaction mixture wasfiltered through Celite and the filtrate was concentrated. The residuewas dissolved in methanol (5 mL). To the solution was added sodiumborohydride (0.14 g), followed by stirring the reaction mixture at roomtemperature for 30 minutes. After addition of 1N aqueous hydrochloricacid solution, the reaction mixture was extracted with ethyl acetatetwice. The organic layer was washed with saturated brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:4) to givespiro[4.5]dec-8-yl-methanol (0.528 g).

¹H-NMR (CDCl₃) δ: 1.00-1.12 (2H, m), 1.23-1.64 (15H, brm), 3.46 (2H, d,J=6.4 Hz).

Step 6

Spiro[4.5]dec-8-yl-methanol (0.528 g) obtained in Step 5 was subjectedto the reaction in the same condition as in Step of Example 1 to give(S)-3-[4-(spiro[4.5]dec-8-ylmethoxy)-phenyl]-hex-4-ynoic acid methylester (1.1 g).

¹H-NMR (CDCl₃) δ: 1.13-1.21 (2H, m), 1.27-1.29 (3H, m), 1.33-1.43 (3H,m), 1.48-1.60 (6H, m), 1.71-1.76 (3H, m), 1.82 (3H, d, J=2.3 Hz), 2.65(1H, dd, J=15.3, 7.0 Hz), 2.75 (1H, dd, J=15.3, 8.5 Hz), 3.66 (3H, s),3.74 (2H, d, J=6.0 Hz), 4.02-4.07 (1H, m), 6.83 (2H, d, J=8.6 Hz), 7.26(2H, d, J=8.6 Hz).

Step 7

(5)-3-[4-(spiro[4.5]dec-8-ylmethoxy)-phenyl]-hex-4-yno is acid methylester (1.3 g) obtained in the same manner as in Step 6 was subjected tothe reaction in the same condition as in Step 9 of Example 1 to give(S)-3-[4-(spiro[4.5]dec-8-ylmethoxy)-phenyl]-hex-4-ynoic acid (1.09 g)as the desired compound.

Example 23 Preparation of(S)-3-[4-(spiro[4.5]dec-8-ylmethoxy)-phenyl]-hex-4-ynoic acid sodiumsalt

In the same manner as in Example 2 or 4, the desired compound wasobtained from the compound obtained in Example 22.

Example 24 Preparation of(S)-3-[4-(spiro[5.5]undec-3-ylmethoxy)-phenyl]-hex-4-ynoic acid Step 1

In the same manner as in Steps 1 to 5 of Example 22,spiro[5.5]undec-3-yl-methanol was obtained from spiro[5.5]undecan-3-oneobtained in Step 2 of Example 1.

¹H-NMR (CDCl₃) δ: 1.12-1.02 (4H, m), 1.26-1.21 (4H, m), 1.42-1.39 (7H,m), 1.57-1.51 (2H, m), 1.68-1.65 (2H, m), 3.47 (2H, brs).

Step 2

In the same manner as in Steps 6 to 7 of Example 22, the desiredcompound was obtained from the compound obtained in the above Step 1.

Example 25 Preparation of(S)-3-[4-(spiro[4.5]dec-7-en-8-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

Spiro[4.5]dec-7-en-8-yl-methanol (0.5 g) obtained in Step 4 of Example22 and (S)-3-(4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (0.803 g)obtained in the same manner as in Substep 5 of Example 1 were subjectedto the reaction in the same condition as in Step 8 of Example 1 to give(S)-3-[4-(spiro[4.5]dec-7-en-8-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (1.05 g).

¹H-NMR (CDCl₃) δ: 1.37-1.40 (4H, m), 1.52-1.56 (2H, m), 1.60-1.65 (4H,m), 1.82 (3H, d, J=2.3 Hz), 1.93-1.96 (2H, m), 2.08-2.13 (2H, m), 2.64(1H, dd, J=15.1, 7.0 Hz), 2.75 (1H, dd, J=15.1, 8.3 Hz), 3.66 (3H, s),4.03-4.08 (1H, m), 4.36 (2H, s), 5.73 (1H, s), 6.85 (2H, d, J=8.6 Hz),7.26 (2H, d, J=8.6 Hz).

Step 2

(S)-3-[4-(spiro[4.5]dec-7-en-8-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (1.0 g) obtained in Step 1 was subjected to the reaction inthe same condition as in Step 9 of Example 1 to give(S)-3-[4-(spiro[4.5]dec-7-en-8-ylmethoxy)-phenyl]-hex-4-ynoic acid(0.924 g) as the desired compound.

Example 26 Preparation of(3S)-3-[4-(spiro[4.5]dec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

To a solution of spiro[4.5]dec-1-en-2-yl-methanol (50 mg) obtained inStep 5 of Example 15 in tetrahydrofuran (1 mL) was added 5% palladiumcarbon (5 mg), followed by stirring the reaction mixture under normalpressure in an atmosphere of hydrogen at room temperature for 20 hours.Then, the reaction mixture was filtered through Celite and the filtratewas concentrated. The residue was dissolved in methanol (1 mL). To thesolution was added sodium borohydride (10 mg), followed by stirring thereaction mixture at room temperature for 1 hour. Then, after addition of1N aqueous hydrochloric acid solution, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed with water,dried and concentrated to give spiro[4.5]dec-2-yl-methanol (30 mg).

¹H-NMR (CDCl₃) δ: 0.95-1.03 (1H, m), 1.31-1.47 (12H, brm), 1.66-1.81(3H, m), 2.13-2.23 (1H, m), 3.53 (2H, d, J=6.8 Hz).

Step 2

Spiro[4.5]dec-2-yl-methanol (30 mg) obtained in Step 1 and(S)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester (52 mg) obtainedin the same manner as in Substep 5 of Example 1 were subjected thereaction in the same condition as in Step 8 of Example 1 to give(3S)-3-[4-(spiro[4.5]dec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid methylester (49 mg).

¹H-NMR (CDCl₃) δ: 1.10 (1H, dd, J=13.0, 9.2 Hz), 1.36-1.49 (10H, m),1.78-1.83 (5H, m), 2.38-2.46 (1H, m), 2.65 (1H, dd, J=15.3, 7.0 Hz),2.75 (1H, dd, J=15.3, 8.5 Hz), 3.66 (3H, s), 3.81 (2H, d, J=6.7 Hz),4.02-4.07 (1H, m), 6.83 (2H, d, J=8.7 Hz), 7.26 (2H, d, J=8.7 Hz).

Step 3

(3S)-3-[4-(spiro[4.5]dec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid methylester (49 mg) obtained in Step 2 was subjected to the reaction in thesame condition as in Step 9 of Example 1 to give(3S)-3-[4-(spiro[4.5]dec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid (20 mg)as the desired compound.

¹H-NMR (CDCl₃) δ: 1.11 (1H, dd, J=12.4, 9.6 Hz), 1.48-1.29 (13H, m),1.85-1.79 (5H, m), 2.44-2.42 (1H, m), 2.84-2.69 (2H, m), 2.84-2.69 (2H,m), 3.82 (2H, d, J=6.5 Hz), 4.06-4.04 (1H, brm), 6.85 (2H, d, J=8.1 Hz),7.28 (2H, d, J=8.1 Hz).

Example 27 Preparation of(3S)-3-[4-(spiro[4.5]dec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodiumsalt

In the same manner as in Example 2 or 4, the desired compound wasobtained from the compound obtained in the same manner as in Example 26.

Example 28 Preparation of(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid Step 1

In the same manner as in Step 1 of Example 26,spiro[5.5]undec-2-yl-methanol was obtained fromspiro[5.5]undec-2-en-2-yl-methanol obtained in the same manner as inStep 7 of Example 1.

¹H-NMR (CDCl₃) δ: 0.65 (1H, t, J=13.2 Hz), 0.75-0.97 (2H, m), 1.81-1.18(16H, m), 3.41 (2H, d, J=4.1 Hz).

Step 2

In the same manner as in Steps 2 to 3 of Example 26, the desiredcompound was obtained from the compound obtained in the above Step 1.

Example 29 Preparation of(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodiumsalt

In the same manner as in Example 27, the desired compound was obtainedfrom the compound obtained in the same manner as in Example 28.

Example 30 Preparation of(3S)-3-[4-(spiro[4.4]non-2-ylmethoxy)-phenyl]-hex-4-ynoic acid Step 1

In the same manner as in Step 1 of Example 26,spiro[4.4]non-2-yl-methanol was obtained fromspiro[4.4]non-1-en-2-yl-methanol obtained in the same manner as in Step1 of Example 17.

¹H-NMR (CDCl₃) δ: 1.18 (1H, td, J=9.0, 3.3 Hz), 1.38-1.31 (1H, m),1.53-1.42 (6H, m), 1.64-1.57 (4H, m), 1.69 (1H, dd, J=12.6, 8.0 Hz),1.85-1.75 (1H, m), 2.22 (1H, tt, J=16.0, 5.3 Hz), 3.54 (2H, d, J=7.0Hz).

Step 2

In the same manner as in Steps 2 to 3 of Example 26, the desiredcompound was obtained from the compound obtained in the above Step 1.

Example 31 Preparation of(3S)-3-[4-(spiro[4.4]non-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodiumsalt

In the same manner as in Example 27, the desired compound was obtainedfrom the compound obtained in Example 30.

Example 32 Preparation of(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid(chiral: A)

Step 1

To a solution of spiro[5.5]undec-2-ene-2-carboxylic acid methyl ester(300 mg) obtained in the same manner as in Step 6 of Example 1 intetrahydrofuran (15 mL) was added 5% palladium carbon (50 mg), followedby stirring the reaction mixture under increased pressure of 0.3 MPa inan atmosphere of hydrogen at room temperature for 4 hours. Then, thereaction mixture was filtered through Celite. The filtrate wasconcentrated in vacuo to give spiro[5.5]undecane-2-carboxylic acidmethyl ester (300 mg).

¹H-NMR (CDCl₃) δ: 0.98 (1H, td, J=13.2, 4.1 Hz), 1.16 (1H, t, J=13.2Hz), 1.22-1.50 (13H, m), 1.65 (1H, d, J=12.3 Hz), 1.82-1.94 (2H, m),2.47 (1H, tt, J=12.3, 3.6 Hz), 3.67 (3H, s).

Step 2

To a solution of spiro[5.5]undecane-2-carboxylic acid methyl ester (500mg) obtained in the same manner as in Step 1 in a mixed solvent oftetrahydrofuran (5 mL)-methanol (5 mL) was added 2N aqueous sodiumhydroxide solution (3.57 mL), followed by stirring the reaction mixtureat 50° C. for 3 hours. After cooling down to room temperature, 2Naqueous hydrochloric acid solution (3.57 mL) was added to the reactionmixture. Methanol in the reaction mixture was evaporated off in vacuo,followed by extraction with ethyl acetate. The organic layer was driedand then concentrated to give spiro[5.5]undecane-2-carboxylic acid (440mg).

Step 3

Toa solution of spiro[5.5]undecane-2-carboxylic acid (570 mg) obtainedin the same manner as in Step 2 in chloroform (6 mL) were added thionylchloride (0.425 mL) and N,N-dimethylformamide (0.06 mL), followed bystirring the reaction mixture at room temperature for 2.5 hours. Then,the reaction mixture was concentrated and the resulting residue wasdissolved in tetrahydrofuran (6 mL). To the solution were addedsuccessively triethylamine (1.21 mL), (R)-4-benzyl-2-oxazolidinone (670mg) and 4-dimethylaminopyridine (35 mg) under ice-cooling, followed bystirring the reaction mixture at room temperature for 12 hours. Then,after addition of ice-cold water, the reaction mixture was extractedwith ethyl acetate. The organic layer was washed with aqueous potassiumhydrogen sulfate solution, dried and concentrated. The residue waspurified by column chromatography on silica gel (hexane:ethyl acetate(volume ratio) 20:1) to give(4R)-4-benzyl-3-(spiro[5.5]undecane-2-carbonyl)-oxazolidin-2-one(less-polar isomer (chiral: A); 430 mg, more-polar isomer (chiral: B);390 mg).

Less-polar isomer (chiral: A):

¹H-NMR (CDCl₃) δ: 0.98-1.06 (1H, m), 1.12-1.29 (3H, m), 1.38-1.63 (11H,m), 1.70 (1H, d, J=13.2 Hz), 1.78-1.85 (1H, m), 1.92 (1H, dd, J=12.6,2.2 Hz), 2.79 (1H, dd, J=13.4, 9.5 Hz), 3.26 (1H, dd, J=13.4, 3.2 Hz),3.67-3.75 (1H, m), 4.14-4.23 (2H, m), 4.65-4.71 (1H, m), 7.22-7.37 (5H,m).

More-polar isomer (chiral: B):

¹H-NMR (CDCl₃) δ: 1.02 (1H, td, J=13.0, 4.6 Hz), 1.18-1.28 (3H, m),1.37-1.66 (11H, m), 1.67-1.82 (2H, m), 1.91-1.98 (1H, m), 2.77 (1H, dd,J=13.2, 9.5 Hz), 3.26 (1H, dd, J=13.2, 3.3 Hz), 3.72 (1H, tt, J=12.1,3.3 Hz), 4.14-4.24 (2H, m), 4.63-4.69 (1H, m), 7.17-7.40 (5H, m).

As used herein, when a carbon atom at the spiro junction is a chiralcarbon as represented by, for example, the following formula:

chiral: A refers to a chirality of a carbon atom at the spiro junctionin a less-polar isomer. Also, the following compounds obtained from thecompounds having the above chirality will be represented by the nameswith (chiral: A) at the end thereof. Similarly, chiral: B refers to achirality of a carbon atom at the spiro junction in a more-polar isomer.Also, the following compounds obtained from the compounds having theabove chirality will be represented by the names with (chiral: B) at theend thereof.

Step 4

To a suspension of lithium aluminum hydride (55 mg) in tetrahydrofuran(5 mL) was added dropwise a solution of(4R)-4-benzyl-3-(spiro[5.5]undecane-2-carbonyl)-oxazolidin-2-one(chiral: A) (425 mg) obtained in Step 3 in tetrahydrofuran (5 mL) underice-cooling and nitrogen atmosphere, followed by stirring the reactionmixture in the range of ice-cooling to room temperature for 1.5 hours.Then, to the reaction mixture were added successively water (0.06 mL),4N aqueous sodium hydroxide solution (0.06 mL) and water (0.18 mL),followed by stirring the reaction mixture at room temperature for 30minutes. The precipitated insolubles in the reaction mixture werefiltered off and the filtrate was concentrated in vacuo. The residue waspurified by column chromatography on silica gel (ethyl acetate:hexane(volume ratio)=1:20 to 1:10) to give spiro[5.5]undec-2-yl-methanol(chiral: A) (185 mg).

¹H-NMR (CDCl₃) δ: 0.65 (1H, t, J=13.2 Hz), 0.75-0.97 (2H, m), 1.81-1.18(16H, m), 3.41 (2H, d, J=4.1 Hz).

Step 5

Spiro[5.5]undec-2-yl-methanol (chiral: A) (100 mg) obtained in Step 4and (S)-3-(4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester obtained inthe same manner as in Substep 5 of Example 1 were subjected to thereaction in the same condition as in Step 8 of Example 1 to give(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid methylester (chiral: A) (200 mg).

¹H-NMR (CDCl₃) δ: 0.76 (1H, t, J=12.6 Hz), 0.86-0.99 (2H, m), 1.30-1.20(3H, m), 1.49-1.37 (9H, m), 1.65-1.79 (2H, m), 1.82 (3H, d, J=2.4 Hz),1.87-1.99 (2H, m), 2.65 (1H, dd, J=15.2, 8.4 Hz), 2.75 (1H, dd, J=15.2,8.4 Hz), 3.65-3.72 (5H, m), 4.03-4.07 (1H, m), 6.83 (2H, d, J=8.4 Hz),7.26 (2H, d, J=8.4 Hz).

Step 6

(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid methylester (chiral: A) (200 mg) obtained in Step 5 was subjected to thereaction in the same condition as in Step of Example 1 to give(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid(chiral: A) (190 mg) as the desired compound.

Example 33 Preparation of(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodiumsalt (chiral: A)

In the same manner as in Example 2 or 4, the desired compound wasobtained from the compound obtained in Example 32.

Example 34 Preparation of(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid(chiral: B) Step 1

In the same manner as in Step 4 of Example 32,spiro[5.5]undec-2-yl-methanol (chiral:B) was obtained from themore-polar isomer (chiral:B) obtained in Step 3 of Example 32.

¹H-NMR (CDCl₃) δ: 0.65 (1H, t, J=13.2 Hz), 0.75-0.97 (2H, m), 1.81-1.18(16H, m), 3.41 (2H, d, J=4.1 Hz).

Step 2

In the same manner as in Steps 5 to 6 of Example 32, the desiredcompound was obtained from the compound obtained in the above Step 1.

Example 35 Preparation of(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodiumsalt (chiral: B)

In the same manner as in Example 33, the desired compound was obtainedfrom the compound obtained in the same manner as in Example 34.

Example 36 Preparation of(3S)-3-[4-(spiro[4.5]dec-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (chiral:A) Step 1

In the same manner as in Steps 1 to 3 of Example 32, less-polar isomer(chiral: A) and more-polar isomer (chiral: B) of(4R)-4-benzyl-3-(spiro[4.5]decane-7-carbonyl)-oxazolidin-2-one wereobtained from spiro[4.5]dec-7-ene-7-carboxylic acid methyl esterobtained from cyclopentanecarbaldehyde in the same manner as in Steps 1to 6 and 6′ of Example 1.

Less-polar isomer (chiral: A):

¹H-NMR (CDCl₃) δ: 1.22-1.75 (15H, m), 1.90-1.96 (1H, m), 2.77 (1H, dd,J=13.2, 9.5 Hz), 3.27 (1H, dd, J=13.2, 3.4 Hz), 3.59-3.67 (1H, m),4.15-4.23 (2H, m), 4.63-4.69 (1H, m), 7.20-7.23 (2H, m), 7.26-7.36 (3H,m)

More-polar isomer (chiral: B):

¹H-NMR (CDCl₃) δ: 1.23-1.83 (16H, m), 2.76 (1H, dd, J=13.2, 9.6 Hz),3.27 (1H, dd, J=13.2, 3.2 Hz), 3.57-3.65 (1H, m), 4.15-4.22 (2H, m),4.65-4.71 (1H, m), 7.20-7.24 (2H, m), 7.25-7.36 (3H, m).

Step 2

In the same manner as in Step 4 of Example 32,spiro[4.5]dec-7-yl-methanol (chiral: A) was obtained from the less-polarisomer (chiral: A) obtained in Step 1.

¹H-NMR (CDCl₃) δ: 0.84 (1H, dddd, J=12.7, 12.7, 12.7, 3.9 Hz), 0.92 (1H,dd, J=12.7, 12.7 Hz), 1.15 (1H, ddd, J=12.7, 12.7, 3.9 Hz), 1.25-1.67(14H, m), 1.71-1.78 (1H, m), 3.43 (2H, t, J=5.1 Hz).

Step 3

In the same manner as in Steps 5 to 6 of Example 32, the desiredcompound was obtained from the compound obtained in Step 2.

Example 37 Preparation of(3S)-3-[4-(spiro[4.5]dec-7-ylmethoxy)-phenyl]-hex-4-ynoic acid sodiumsalt (chiral: A)

In the same manner as in Example 33, the desired compound was obtainedfrom the compound obtained in Example 36.

Example 38 Preparation of(3S)-3-[4-(spiro[4.5]dec-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (chiral:B) Step 1

In the same manner as in Step 4 of Example 32,spiro[4.5]dec-7-yl-methanol (chiral: B) was obtained from the more-polarisomer (chiral: B) obtained in Step 1 of Example 36.

¹H-NMR (CDCl₃) δ: 0.84 (1H, dddd, J=12.7, 12.7, 12.7, 3.9 Hz), 0.92 (1H,dd, J=12.7, 12.7 Hz), 1.15 (1H, ddd, J=12.7, 12.7, 3.9 Hz), 1.24-1.67(14H, m), 1.71-1.78 (1H, m), 3.43 (2H, brs).

Step 2

In the same manner as in Steps 5 to 6 of Example 32, the desiredcompound was obtained from the compound obtained in the above Step 1.

Example 39 Preparation of(3S)-3-[4-(spiro[4.5]dec-7-ylmethoxy)-phenyl]-hex-4-ynoic acid sodiumsalt (chiral: B)

In the same manner as in Example 33, the desired compound was obtainedfrom the compound obtained in Example 38.

Example 40 Preparation of3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionicacid

Step 1

To a solution of 3-(4-hydroxyphenyl)-hex-4-ynoic acid (3.0 g) obtainedin the same manner as in Substep 3 of Example 1 in a mixed solvent oftoluene (30 mL)-methanol (10 mL) was added dropwise a hexane solution oftrimethylsilyldiazomethane (2M, 8.8 mL) under ice-cooling over 8minutes, followed by stirring the reaction mixture at room temperaturefor 2 hours. Then, the reaction mixture was concentrated and the residuewas dissolved in chloroform (60 mL). To the solution were addedsuccessively 3,4-dihydro-2H-pyrane (1.6 mL) and camphorsulfonic acid(0.17 g) under ice-cooling, followed by stirring the reaction mixtureunder ice-cooling for 2 hours. Then, after addition of saturated aqueoussodium bicarbonate solution to the reaction mixture, methanol wasevaporated off in vacuo, followed by extraction with ethyl acetate. Theorganic layer was washed with saturated brine, dried and concentrated.The residue was purified by column chromatography on silica gel (ethylacetate:hexane (volume ratio)=1:4 to 1:3) to give3-[4-(tetrahydropyran-2-yloxy)-phenyl]-hex-4-ynoic acid methyl ester(4.07 g).

¹H-NMR (CDCl₃) δ: 1.57-1.73 (3H, m), 1.82-1.89 (5H, m), 1.96-2.06 (1H,m), 2.66 (1H, dd, J=15.3, 7.0 Hz), 2.76 (1H, dd, J=15.3, 8.6 Hz),3.59-3.61 (1H, m), 3.68 (3H, s), 3.87-3.94 (1H, m), 4.05-4.09 (1H, m),5.40 (1H, t, J=3.3 Hz), 7.00 (2H, d, J=8.6 Hz), 7.28 (2H, d, J=8.6 Hz).

Step 2

To a solution of 3-[4-(tetrahydropyran-2-yloxy)-phenyl]-hex-4-ynoic acidmethyl ester (4.07 g) obtained in Step 1 in ethyl acetate (70 mL) wereadded successively quinoline (1.52 mL) and 5% palladium-barium sulfate(0.4 g), followed by stirring the reaction mixture under normal pressurein an atmosphere of hydrogen at room temperature for 15.5 hours. Then,after the reaction mixture was filtered through Celite, water and 1Naqueous hydrochloric acid solution were added to the filtrate, followedby extraction with ethyl acetate. The organic layer was washedsuccessively with 1N aqueous hydrochloric acid solution and saturatedbrine, dried and concentrated to give(Z)-3-[4-(tetrahydropyran-2-yloxy)-phenyl]-hex-4-enoic acid methyl ester(3.83 g).

Step 3

To a solution of (Z)-3-[4-(tetrahydropyran-2-yloxy)-phenyl]-hex-4-enoicacid methyl ester (3.83 g) obtained in Step 2 in a mixed solvent ofdioxane (60 mL)-water (15 mL) was added 2,6-lutidine (2.8 mL). Then, tothis was added dropwise a tert-butanol solution of osmium tetroxide (5mg/mL, 12 mL) over 5 minutes, followed by stirring the reaction mixtureat room temperature for 3 minutes. Then, to the reaction mixture wasadded dropwise aqueous sodium periodate solution (10.3 g/25 mL) over 7minutes, followed by stirring the reaction mixture at room temperaturefor 2 hours. After addition of ethyl acetate to the reaction mixture,the organic layer was separated. The organic layer was washedsuccessively with 1N aqueous hydrochloric acid solution, water,saturated aqueous sodium bicarbonate solution, saturated aqueous sodiumthiosulfate solution and saturated brine, dried and concentrated. Theresidue was purified by column chromatography on silica gel (ethylacetate:hexane (volume ratio)=1:4 to 1:3) to give4-oxo-3-[4-(tetrahydropyran-2-yloxy)-phenyl]-butyric acid methyl ester(2.59 g).

¹H-NMR (CDCl₃) δ: 1.57-1.72 (3H, m), 1.84-1.88 (2H, m), 1.95-2.03 (1H,m), 2.58 (1H, dd, J=16.9, 6.2 Hz), 3.13 (1H, dd, J=16.9, 8.3 Hz),3.58-3.64 (1H, m), 3.66 (3H, s), 3.85-3.93 (1H, m), 4.15-4.07 (1H, m),5.41 (1H, q, J=3.1 Hz), 7.04-7.12 (4H, m), 9.67 (1H, s).

Step 4

To a solution of 4-oxo-3-[4-(tetrahydropyran-2-yloxy)-phenyl]-butyricacid methyl ester (1.29 g) obtained in Step 3 in methanol (13 mL) wasadded camphorsulfonic acid (98 mg), followed by stirring the reactionmixture at room temperature for 6 hours. Then, after addition of 1Naqueous sodium hydroxide solution (0.42 mL), the reaction mixture wasconcentrated. To the residue was added water, followed by extractionwith ethyl acetate. The organic layer was washed with saturated brine,dried and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:2 to2:3) to give 3-(4-hydroxyphenyl)-4,4-dimethoxy butyric acid methyl ester(0.99 g).

¹H-NMR (CDCl₃) δ: 2.60 (1H, dd, J=15.7, 9.0 Hz), 2.85 (1H, dd, J=15.7,5.7 Hz), 3.29 (3H, s), 3.39-3.43 (1H, m), 3.58 (3H, s), 4.38 (1H, d,J=6.0 Hz), 4.95 (1H, s), 6.74 (2H, d, J=9.2 Hz), 7.12 (2H, d, J=9.2 Hz).

Step 5

To a solution of 3-(4-hydroxyphenyl)-4,4-dimethoxy butyric acid methylester (0.257 g) obtained in Step 4 and 2-bromomethyl-spiro[5.5]undecane(0.225 g) obtained in the following Substep 1 in N,N-dimethylformamide(3 mL) was added cesium carbonate (0.597 g), followed by stirring thereaction mixture at 80° C. for 2.5 hours. Then, after addition of water,the reaction mixture was extracted with ethyl acetate. The organic layerwas washed successively with water and saturated brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:20 to 1:6) to give4,4-dimethoxy-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-butyric acidmethyl ester (0.297 g).

Step 6

To a solution of4,4-dimethoxy-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-butyric acidmethyl ester (820 mg) obtained in the same manner as in Step 5 inacetone (8 mL), trifluoroacetic acid (6 mL) was added in three portionshourly, followed by stirring the reaction mixture at room temperaturefor 3 hours. Then, after addition of saturated aqueous sodiumbicarbonate solution under ice-cooling, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed successivelywith saturated aqueous sodium bicarbonate solution and saturated brine,dried and concentrated to give a crude aldehyde. To a solution of thecrude aldehyde in a mixed solvent of tert-butanol (6 mL)-water (1.5 mL)were added successively sodium dihydrogen phosphate (88 mg),2-methyl-2-butene (0.3 mL) and sodium chlorite (218 mg), followed bystirring the reaction mixture at room temperature for 1 hour. Then,after addition of 1N aqueous hydrochloric acid solution, the reactionmixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, dried and concentrated to give2-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succinic acid 4-methyl ester(310 mg).

Step 7

To a solution of 2-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succinicacid 4-methyl ester (310 mg) obtained in Step 6 in N,N-dimethylformamide(4 mL) were added successively1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (163 mg),1-hydroxybenzotriazole hydrate (115 mg) and a tetrahydrofuran solutionof methylamine (2M, 0.53 mL), followed by stirring the reaction mixtureat room temperature for 13 hours. Then, after addition of water, thereaction mixture was extracted with ethyl acetate. The organic layer waswashed successively with 1N aqueous hydrochloric acid solution, water,saturated aqueous sodium bicarbonate solution and saturated brine, driedand concentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:1) to giveN-methyl-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succinamic acidmethyl ester (278 mg).

¹H-NMR (CDCl₃) δ: 0.77 (1H, t, J=15.1 Hz), 0.88-1.02 (2H, m), 1.21-1.29(2H, m), 1.38-1.54 (10H, m), 1.66-2.02 (4H, m), 2.61 (1H, dd, J=16.6,6.3 Hz), 2.75 (3H, d, J=4.4 Hz), 3.28 (1H, dd, J=16.6, 8.5 Hz), 3.66(3H, s), 3.70 (2H, dd, J=5.6, 2.8 Hz), 3.87 (1H, dd, J=8.6, 6.3 Hz),5.36-5.43 (1H, m), 6.86 (2H, d, J=8.1 Hz), 7.19 (2H, d, J=8.1 Hz).

Step 8

To a solution ofN-methyl-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succinamic acidmethyl ester (178 mg) obtained in Step 7 in acetonitrile (5 mL) wereadded successively sodium azide (85 mg) and trifluoromethanesulfonicanhydride (0.29 mL), followed by stirring the reaction mixture at roomtemperature for 24 hours. Then, after addition of saturated aqueoussodium bicarbonate solution, the reaction mixture was extracted withethyl acetate. The organic layer was washed with brine, dried andconcentrated. The residue was purified by thin-layer columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:1)to give3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionicacid methyl ester (41 mg).

¹H-NMR (CDCl₃) δ: 0.75 (1H, t, J=12.1 Hz), 0.86-0.99 (2H, m), 1.19-1.28(2H, m), 1.36-1.99 (14H, m), 3.00 (1H, dd, J=17.4, 5.5 Hz), 3.53 (1H,dd, J=17.4, 8.8 Hz), 3.63-3.70 (5H, m), 3.82 (3H, s), 4.57 (1H, dd,J=5.5, 8.8 Hz), 6.83 (2H, d, J=8.4 Hz), 7.11 (2H, d, J=8.4 Hz).

Step 9

To a solution of3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmetboxy)-phenyl]-propionic acid methyl ester (41 mg) obtained in Step 8 ina mixed solvent of tetrahydrofuran (1 mL)-methanol (0.5 mL)-water (0.5mL) was added 2N aqueous sodium hydroxide solution (0.144 mL), followedby stirring the reaction mixture at room temperature for 18 hours. Then,after addition of 1N aqueous hydrochloric acid solution (0.3 mL), thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried and concentrated. The residue waspurified by thin-layer column chromatography on silica gel (aceticacid:ethyl acetate:chloroform (volume ratio)=0.1:1:10) to give3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmetboxy)-phenyl]-propionic acid (39 mg) as the desired compound.

Substep 1

To a solution of spiro[5.5]undec-2-ylmethanol (0.65 g) obtained in thesame manner as in Step 1 of Example 26 fromspiro[5.5]undec-2-en-2-yl-methanol obtained in the same manner as inStep 7 of Example 1, in chloroform (10 mL) were added successivelytriphenylphosphine (1.12 g) and N-bromosuccinimide (0.76 g), followed bystirring the reaction mixture at room temperature for 19 hours. Then,after addition of hexane, the precipitate was filtered off and thefiltrate was concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:4)to give 2-bromomethyl-spiro[5.5]undecane (0.83 g).

¹H-NMR (CDCl₃) δ: 0.69 (1H, t, J=13.2 Hz), 0.81-0.96 (2H, m), 1.19-1.24(2H, m), 1.91-1.36 (14H, m), 3.25 (2H, d, J=5.7 Hz).

Example 41 Preparation of3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid

Step 1

To a suspension of potassium tert-butoxide (24.4 g) in toluene (100 mL)was added a solution of cyclohexanone (10.67 g) and 1,5-dibromopentane(25 g) in toluene (50 mL) while stirring. The mixture was stirred at100° C. for 4 hours. After cooling down to room temperature, theresulting solid was filtered and washed with toluene. The filtrate wasconcentrated and the residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:15) to givespiro[5.5]undecan-1-one (11.85 g).

¹H-NMR (CDCl₃) δ: 1.30-1.51 (8H, m), 1.66-1.74 (4H, m), 1.79-1.91 (4H,m), 2.38 (2H, t, J=6.8 Hz).

Step 2

To a suspension of 60% sodium hydride (5.7 g) and potassiumtert-butoxide (1.6 g) in tetrahydrofuran (200 mL) was added dimethylcarbonate (9.6 mL) at room temperature while stirring. The reactionmixture was heated under reflux. To the reaction mixture was addeddropwise a solution of spiro[5.5]undecan-1-one (11.85 g) obtained inStep 1 in tetrahydrofuran (40 mL) over 1 hour, followed by heating thereaction mixture under reflux for 2 hours. After ice-cooling, aceticacid (14.6 mL) was added dropwise to the reaction mixture. Then, thereaction mixture was poured into saturated brine, followed by extractionwith ethyl acetate. The organic layer was washed with saturated brine,dried and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:15)to give 1-oxo-spiro[5.5]undecane-2-carboxylic acid methyl ester (13.02g).

¹H-NMR (CDCl₃) δ: 1.29-1.74 (8H, m), 1.78-1.98 (6H, m), 2.16-2.22 (2H,m), 3.74 (3H, s), 12.64 (1H, m).

Step 3

To a solution of 1-oxo-spiro[5.5]undecane-2-carboxylic acid methyl ester(13.02 g) obtained in Step 2 in methanol (300 mL), sodium borohydride(2.2 g) was added in small portions under ice-cooling, followed bystirring the reaction mixture under ice-cooling for 30 minutes. Then,after addition of saturated brine, 2N aqueous hydrochloric acid solutionwas further added dropwise to the reaction mixture until the evolutionof gases ceased, followed by extraction with ethyl acetate twice. Theorganic layer was washed with saturated brine, dried and concentrated.The residue was purified by column chromatography on silica gel (ethylacetate:hexane (volume ratio)=1:8 to 1:5) to givetrans-1-hydroxy-spiro[5.5]undecane-2-carboxylic acid methyl ester (2.74g).

¹H-NMR (CDCl₃) δ: 0.82 (1H, tt, J=13.6, 5.0 Hz), 1.07-1.22 (2H, m),1.31-1.67 (10H, m), 1.84-2.01 (2H, m), 2.17 (1H, dt, J=12.0, 4.2 Hz),2.39 (1H, d, J=4.4 Hz), 2.52-2.59 (1H, m), 3.42 (1H, dd, J=10.7, 4.2Hz), 3.71 (3H, s).

Step 4

To a solution of trans-1-hydroxy-spiro[5.5]undecane-2-carboxylic acidmethyl ester (2.74 g) obtained in Step 3 in chloroform (20 mL) was addedtriethylamine (2.02 mL). To the reaction mixture was added dropwise asolution of methanesulfonyl chloride (1.03 mL) in chloroform (5 mL)under ice-cooling, followed by stirring the reaction mixture at roomtemperature overnight. Then, after addition of water, the reactionmixture was washed therewith. The separated organic layer was dried andconcentrated. To the residue were added tetrahydrofuran (30 mL) and1,8-diazabicyclo[5.4.0]undec-7-ene (3.62 mL), followed by heating thereaction mixture at 60° C. for 3 hours. After cooling down to roomtemperature, the reaction mixture was poured into water, followed byextraction with ethyl acetate. The organic layer was washed successivelywith 1N aqueous hydrochloric acid solution and saturated brine, driedand concentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:8) to givespiro[5.5]undec-1-ene-2-carboxylic acid methyl ester (2.075 g).

¹H-NMR (CDCl₃) δ: 1.32-1.65 (14H, m), 2.20-2.27 (2H, m), 3.73 (3H, s),6.84 (1H, s).

Step 5

To a solution of spiro[5.5]undec-1-ene-2-carboxylic acid methyl ester(2.07 g) obtained in Step 4 in tetrahydrofuran (30 mL) was addeddropwise a 1M toluene solution of diisobutylaluminum hydride (30 mL) at−70° C. under argon atmosphere over 15 minutes, followed by stirring thereaction mixture at −70° C. for 1 hour. Then after careful addition ofmethanol (2 mL) and 6N aqueous hydrochloric acid solution (5 mL) to thereaction mixture, the temperature was raised to room temperature. Thereaction mixture was poured into saturated brine, followed by extractionwith ethyl acetate. The organic layer was washed with saturated brine,dried and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:5)to give spiro[5.5]undec-1-ene-2-methanol (1.685 g).

¹H-NMR (CDCl₃) δ: 1.24-1.53 (12H, m), 1.55-1.57 (1H, m), 1.62 (2H, tt,J=9.2, 3.1 Hz), 1.97 (2H, t, J=6.2 Hz), 3.99 (2H, d, J=6.0 Hz), 5.55(1H, s).

Step 6

To a solution of spiro[5.5]undec-1-ene-2-methanol (3.189 g) obtained inthe same manner as in Step 5, 4-hydroxybenzaldehyde (2.589 g) andtriphenylphosphine (5.56 g) in tetrahydrofuran (100 mL) was addeddropwise a solution of 94% 1,1′-diisopropyl azodicarboxylate (4.446 mL)in tetrahydrofuran (3 mL) under ice-cooling, followed by stirring thereaction mixture at room temperature overnight. Then, the reactionmixture was concentrated and the residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:9)to give 4-(spiro[5.5]undec-1-en-2-ylmethoxy)-benzaldehyde (4.27 g).

¹H-NMR (CDCl₃) δ: 1.24-1.51 (12H, m), 1.60-1.68 (2H, m), 2.03 (2H, dt,J=6.2, 2.7 Hz), 4.46 (2H, s), 5.70 (1H, s), 7.01 (2H, dt, J=9.3, 2.3Hz), 7.82 (2H, dt, J=9.3, 2.3 Hz), 9.89 (1H, s).

Step 7

To a solution of ethyl acetate (2.2 mL) in tetrahydrofuran (100 mL) wasadded dropwise a 2M heptane/tetrahydrofuran/ethylbenzene solution oflithium diisopropylamide (11.25 mL) at −78° C. under argon atmosphereover 15 minutes, followed by stirring the reaction mixture at −78° C.for 30 minutes. Then, to the reaction mixture was added dropwise asolution of 4-(spiro[5.5]undec-1-en-2-ylmethoxy)-benzaldehyde (4.27 g)obtained in Step 6 in tetrahydrofuran (15 mL) over 10 minutes, followedby stirring the reaction mixture at −78° C. for 40 minutes. After thetemperature was raised to room temperature, saturated aqueous ammoniumchloride solution (100 mL) was added carefully to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine, dried and concentrated. The residue was purifiedby column chromatography on silica gel (ethyl acetate:hexane (volumeratio)=1:4 to 1:3) to give3-hydroxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acidethyl ester (4.98 g).

¹H-NMR (CDCl₃) δ: 1.26 (3H, dq, J=10.4, 2.7 Hz), 1.30-1.49 (8H, m), 1.54(2H, s), 1.64 (2H, tt, J=9.2, 3.1 Hz), 2.01-2.04 (4H, m), 2.67 (1H, dd,J=16.2, 3.9 Hz), 2.75 (1H, dd, J=16.4, 9.3 Hz), 3.11 (1H, d, J=3.4 Hz),4.15-4.22 (2H, m), 4.36 (2H, s), 5.08 (1H, dt, J=9.1, 3.4 Hz), 5.67 (1H,s), 6.90 (2H, dt, J=9.3, 2.5 Hz), 7.25-7.29 (2H, m).

Step 8

To a solution of3-hydroxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acidethyl ester (4.98 g) obtained in Step 7 and N,N-diisopropylethylamine(6.97 mL) in chloroform (100 mL) was added dropwise a 1M dichloromethanesolution of triethyloxonium tetrafluoroborate (20 mL) under ice-coolingover 5 minutes, followed by stirring the reaction mixture underice-cooling for 10 minutes and then at room temperature for 2.5 hours.Then, the reaction mixture was concentrated and the residue wasextracted with ethyl acetate. The organic layer was washed successivelywith water and saturated brine, dried and concentrated. The residue waspurified by column chromatography on silica gel (ethyl acetate:hexane(volume ratio)=1:5) to give3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acidethyl ester (2.175 g).

¹H-NMR (CDCl₃) δ: 1.13 (3H, t, J=7.0 Hz), 1.22 (3H, td, J=7.6, 3.1 Hz),1.31-1.50 (10H, m), 1.53 (2H, d, J=4.8 Hz), 1.64 (2H, tt, J=9.2, 3.1Hz), 2.06 (2H, dt, J=12.8, 7.1 Hz), 2.5 (1H, dd, J=15.0, 5.1 Hz), 2.79(1H, dd, J=15.0, 8.9 Hz), 3.28-3.41 (2H, m), 4.12 (2H, ddd, J=14.3, 7.1,2.1 Hz), 4.35 (2H, s), 4.68 (1H, dd, J=8.9, 5.1 Hz), 5.67 (1H, s), 6.89(2H, dt, J=9.2, 2.4 Hz), 7.23 (2H, dt, J=9.2, 2.4 Hz).

Step 9

To a solution of3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acidethyl ester (3.169 g) obtained in the same manner as in Step 8 in amixed solvent of ethanol (10 mL)-tetrahydrofuran (10 mL) was added 4Naqueous sodium hydroxide solution (4 mL) under ice-cooling, followed bystirring the reaction mixture at room temperature for 10 minutes. Then,after addition of ethanol (5 mL) and tetrahydrofuran (5 mL), thereaction mixture was stirred at room temperature overnight. Then, thereaction mixture was diluted with saturated brine and 2N aqueoushydrochloric acid solution (8 mL) was added thereto, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine, dried and concentrated to give3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid(2.95 g).

Example 42 Preparation of(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl ]-propionicacid

Step 1

To a solution of3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid(2.95 g) obtained in Example 41 and triethylamine (3.3 mL) intetrahydrofuran (60 mL) was added dropwise a solution of pivaloylchloride (1.265 mL) in tetrahydrofuran (5 mL) at −35° C., followed bystirring the reaction mixture at −35 to −30° C. for 30 minutes. Then, tothe reaction mixture was added dropwise a solution of(R)-4-benzyl-2-oxazolidinone (1.82 g) and lithium bromide (892 mg) intetrahydrofuran (10 mL), followed by raising the temperature up to 0° C.over 2 hours while stirring the reaction mixture. The reaction mixturewas poured into ice-cold water, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried andconcentrated. The residue was purified by mid-pressure preparativechromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:5)to give(R)-4-benzyl-3-{3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionyl}oxazolidin-2-one.

Less-polar diastereomer (1.24 g)

¹H-NMR (CDCl₃) δ: 1.14 (3H, t, J=7.0 Hz), 1.34-1.54 (15H, m), 1.64 (2H,tt, J=9.2, 3.1 Hz), 2.02-2.10 (1H, m), 2.78 (1H, dd, J=13.5, 9.4 Hz),3.10 (1H, dd, J=16.1, 5.0 Hz), 3.29 (1H, dd, J=13.5, 3.1 Hz), 3.37 (2H,ddt, J=16.5, 7.0, 2.7 Hz), 3.67 (1H, dd, J=16.2, 8.7 Hz), 4.36 (2H, s),4.62-4.68 (1H, m), 4.82 (1H, dd, J=8.7, 5.1 Hz), 5.67 (1H, s), 6.88-6.92(2H, m), 7.21-7.36 (7H, m).

More-polar diastereomer (1.18 g)

¹H-NMR (CDCl₃) δ: 1.14 (3H, t, J=7.12 Hz), 1.34-1.49 (9H, m), 1.55 (2H,s), 1.64 (2H, tt, J=9.2, 3.1 Hz), 2.04 (2H, q, J=3.5 Hz), 2.70 (1H, dd,J=13.4, 9.5 Hz), 3.18 (1H, dd, J=16.2, 4.1 Hz), 3.25 (1H, dd, J=13.4,3.3 Hz), 3.34-3.41 (2H, m), 3.50 (1H, dd, J=16.2, 9.4 Hz), 4.18 (2H, dt,J=12.6, 5.0 Hz), 4.36 (2H, s), 4.67-4.72 (1H, m), 4.84 (1H, dd, J=9.4,4.1 Hz), 5.67 (1H, s), 6.90 (2H, dt, J=9.3, 2.4 Hz), 7.15-7.18 (2H, m),7.27-7.34 (5H, m).

Step 2

To a solution of(R)-4-benzyl-3-{3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionyl}oxazolidin-2-one(more-polar diastereomer 1.178 g) obtained in Step 1 in tetrahydrofuran(20 mL) and water (5 mL) was added a mixture of 4N aqueous lithiumhydroxide solution (1.1 mL) and 30% hydrogen peroxide solution (0.88 mL)under ice-cooling, followed by stirring the reaction mixture at roomtemperature. After 1.5 and 5.5 hours, to the reaction mixture wasfurther added a mixture of 4N aqueous lithium hydroxide solution (0.55mL) and 30% hydrogen peroxide solution (0.44 mL), followed by stirringthe reaction mixture at room temperature. After 7 hours, to the reactionmixture were added successively sodium sulfite (2.785 g) and an aqueouspotassium hydrogen sulfate (1.2 g) solution (30 mL) under ice-cooling,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine, dried and concentrated. The residue was purifiedby column chromatography on silica gel (ethyl acetate:hexane (volumeratio)=1:3) to give(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionicacid (443 mg) as the desired compound.

The specific optical rotation of this compound was as follows.

[α]D²⁵=−33.3° (c1.020,EtOH)

Example 43 Preparation of(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionicacid sodium salt

In the same manner as in Example 2 or 4, the desired compound wasobtained from the compound obtained in Example 42.

Example 44 Preparation of(+)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionicacid

In the same manner as in Step 2 of Example 42, the desired compound wasobtained from the less-polar diastereomer obtained in Step 1 of Example42.

Examples 45 to 89

The compounds shown in Tables 1 to 13 were prepared by the samepreparation method as in any of Examples 1 to 44.

Example 90 Preparation of(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid 0.5calcium salt

To a solution of(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt (2.33 g) obtained in the same manner as in Example 2 inwater (60 mL) was added 0.1M aqueous calcium chloride solution (30 mL),followed by stirring the mixture at room temperature for 1 hour. Theprecipitate was filtered and dried to give(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid 0.5calcium salt (1.82 g).

Example 91 Preparation of(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid 0.5calcium salt

To a solution of(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidsodium salt (2.50 g) obtained in the same manner as in Example 8 inwater (35 mL) were added successively 0.1M. aqueous calcium chloridesolution (33.4 mL) and water (20 mL), followed by stirring the mixtureat room temperature for 0.5 hour. The precipitate was filtered and driedto give (S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid 0.5 calcium salt (2.47 g).

Example 92 Preparation of(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidL-lysine salt

To a solution of(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (82.5mg) obtained in the same manner as in Example 7 in 2-propanol (1.75 mL)was added a solution of L-lysine (32.5 mg) in water (0.14 mL) at 60° C.The mixture was stirred at 50° C. for 12 hours and then stirred at roomtemperature for 8 hours. The precipitate was filtered, washed with2-propanol and dried to give(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidL-lysine salt (87.8 mg).

Example 93 Preparation of(R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

To a solution of 3-(4-hydroxyphenyl)-hex-4-ynoic acid (100 mg) obtainedin the same manner as in Substep 3 of Example 1 in 2-propanol (2 mL) wasadded (R)-α-methylbenzylamine (58 mg) at 85° C. The mixture was stirredsuccessively at 85° C. for 0.5 hour, at 40° C. for 2 hours and at roomtemperature overnight. The resulting crystal was filtered and then driedto give (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid (R)-α-methylbenzylaminesalt (68 mg, 66% ee). Meanwhile, to a solution of(R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid (300 g, 58% ee), which has beenobtained by concentration of the filtrate by produced in the same manneras upon recrystallization in Substep 4 of Example 1 and extraction ofthe concentrate under acidic condition in the same manner as uponcrystallization in Substep 4 of Example 1, in 2-propanol (6 L),(R)-α-methylbenzylamine (151 g) was added at 75° C. This solution washeated at 80° C. and (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid(R)-α-methylbenzylamine salt (30 mg) obtained earlier was added thereto.The mixture was stirred at 80° C. for 2 hours, and further stirred for20 hours while gradually cooling down to room temperature. The resultingcrystal was filtered and then dissolved in 2-propanol (5.5 L) whileheating. The mixture was stirred at 65° C. for 4 hours, and furtherstirred overnight while gradually cooling down to room temperature. Theresulting crystal was filtered and dried to give(R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid (R)-α-methylbenzylamine salt(181 g, 98% ee). The optical purity was determined by chiral HPLCanalysis (column: DaicelChiralpakAD-RH, mobile phase: 15 v/v % aqueousacetonitrile solution containing 0.01% trifluoroacetic acid).

¹H-NMR (DMSO-d₆) δ: 1.28 (3H, d, J=6.5 Hz), 1.75 (3H, d, J=3.0 Hz),2.32-2.55 (2H, m), 3.88 (1H, ddd, J=8.0, 3.0, 8.5 Hz), 4.04 (1H, q,J=6.5 Hz), 6.67 (2H, d, J=9.0 Hz), 7.12 (2H, d, J=8.5 Hz), 7.17-7.25(1H, m), 7.27-7.35 (2H, m), 7.35-7.42 (2H, m).

Step 2

(R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid (R)-α-methylbenzylamine salt(40 g) obtained in Step 1 was suspended in ethyl acetate (300mL)-saturated aqueous potassium hydrogen sulfate solution (30 mL). Thesuspension was vigorously stirred until it became a solution, followedby extraction of the reaction mixture with ethyl acetate twice. Theorganic layer was washed successively with water and saturated brine,dried and concentrated to give (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid(25 g).

¹H-NMR (DMSO-d₆) δ: 1.76 (3H, brs), 2.55 (2H, d, J=7.7 Hz), 3.87 (1H, t,J=7.7 Hz), 6.68 (2H, dd, J=8.6, 1.4 Hz), 7.13 (2H, dd, J=8.6, 1.2 Hz),9.28 (1H, s), 12.20 (1H, s).

Step 3

To a solution of (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid (25 g)obtained in Step 2 in methanol (125 mL) was added concentrated sulfuricacid (1.25 mL), followed by stirring the mixture at 80° C. for 2.5hours. After cooling down to room temperature, water (100 mL) and sodiumbicarbonate (4.14 g) were added to the reaction mixture, followed byconcentration of the mixture. To the reaction mixture were added waterand saturated aqueous sodium bicarbonate solution, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine, dried and concentrated. The residue was distilledazeotropically with toluene to give (R)-3-(4-hydroxyphenyl)-hex-4-ynoicacid methyl ester (28.5 g).

¹H-NMR (CDCl₃) δ: 1.84 (3H, d, J=2.6 Hz), 2.66 (1H, dd, J=15.2, 7.1 Hz),2.77 (1H, dd, J=15.3, 8.3 Hz), 3.67 (3H, s), 4.03-4.09 (1H, m), 4.80(1H, s), 6.78 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz).

Step 4

To a solution of (R)-3-(4-hydroxyphenyl)-hex-4-ynoic acid methyl ester(15 g) obtained in Step 3 and 7-bromomethyl-spiro[4.5]dec-6-ene (17.3 g)obtained in the following Substep in N,N-dimethylformamide (150 mL) wasadded potassium carbonate (12.4 g), followed by stirring the reactionmixture at room temperature for 19 hours. To the reaction mixture wasadded water, followed by extraction with n-hexane twice. The organiclayers were combined, washed successively with water and saturatedbrine, dried and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:100to 1:30) to give(R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (23.5 g).

¹H-NMR (CDCl₃) δ: 1.45-1.48 (6H, m), 1.62-1.69 (6H, m), 1.82 (3H, d,J=2.4 Hz), 2.03 (2H, brdd, J=6.3, 6.3 Hz), 2.65 (1H, dd, J=15.2, 7.0Hz), 2.75 (1H, dd, J=15.2, 8.2 Hz), 3.66 (3H, s), 4.02-4.08 (1H, m),4.33 (2H, s), 5.58 (1H, s), 6.84-6.88 (2H, m), 7.24-7.27 (2H, m).

Step 5

To a solution of(R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidmethyl ester (23.5 g) obtained in Step 4 in a mixed solvent oftetrahydrofuran (94 mL)-methanol (94 mL) was added 2N aqueous sodiumhydroxide solution (48 mL), followed by stirring the mixture at roomtemperature overnight. To the reaction mixture was added 2N aqueoushydrochloric acid solution (48 mL), followed by extraction with n-hexanetwice. The organic layers were combined, washed with saturated brine,dried and concentrated to give(R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (26g).

Substep

To a solution of spiro[4.5]dec-6-ene-7-methanol (21.1 g) obtained in thesame manner as in Step 6 of Example 7 in tetrahydrofuran (320 mL) wasadded triethylamine (1.25 mL) under ice-cooling, and then to this wasadded dropwise methanesulfonyl chloride (10.8 mL), followed by stirringthe mixture under ice-cooling for 1.5 hours. To the reaction mixture wasadded lithium bromide (33 g), followed by stirring the mixture underice-cooling for 2 hours. To the reaction mixture was added water,followed by extraction with n-hexane. The organic layer was washed withsaturated brine, dried and concentrated to give7-bromomethyl-spiro[4.5]dec-6-ene (29.2 g) ¹H-NMR (DMSO-d₆) δ: 1.31-1.46(6H, m), 1.53-1.68 (6H, m), 1.98-2.06 (2H, m), 4.07 (2H, s), 5.72 (1H,s).

Example 94 Preparation of(R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acidL-lysine salt

To a solution of(R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid (5.0g) obtained in Example 93 in 2-propanol (75 mL) was added a solution ofL-lysine (2.07 g) in water (5.75 mL) at 70° C., followed by stirringovernight while gradually cooling the mixture down to room temperature.The precipitate was filtered and then dried to give(R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-yno is acidL-lysine salt (5.64 g).

Example 95 Preparation of(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionicacid 0.5 calcium salt

To a solution of(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionicacid sodium salt (3.71 g) obtained in the same manner as in Example 43in water (70 mL) was added 0.1M. aqueous calcium chloride solution (47.1mL), followed by stirring the mixture at room temperature for 0.5 hour.The precipitate was filtered and then dried to give(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionicacid 0.5 calcium salt (3.60 g).

Example 96 Preparation of(3S)-3-[4-((5S)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid

In the same manner as in Example 102,(3S)-3-[4-((5S)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid (40 mg) was obtained from(3S)-3-[4-((2S,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (120 mg) obtained in Step 3 of Example 98.

Example 97 Preparation of(3S)-3-[4-((5S)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid sodium salt

To a solution of(3S)-3-[4-((5S)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid (82 mg) obtained in the same manner as in Example 96 in a mixedsolvent of ethanol (5 mL)-water (1 mL) was added dropwise 0.1N aqueoussodium hydroxide solution (2.13 mL) at −10° C., followed by stirring thereaction mixture at −10° C. for 15 minutes. The reaction mixture wasconcentrated and the residue was distilled azeotropically with ethanol.The residue was dried in vacuo to give(3S)-3-[4-((5S)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid sodium salt (87 mg).

Example 98 Preparation of(3S)-3-[4-((2S,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid

Step 1

To a solution of (S)-1,4-dibromo-2-butanol (5.0 g) inN,N-dimethylformamide (30 mL) were added imidazole (1.91 g) andtert-butylchlorodiphenylsilane (7.1 mL) under ice-cooling, followed bystirring the mixture at room temperature for 13 hours. To the reactionmixture were further added imidazole (0.59 g) andtert-butylchlorodiphenylsilane (1.77 mL), followed by stirring themixture at room temperature for 7 hours. To the reaction mixture wasadded water, followed by extraction with ethyl acetate. The organiclayer was washed successively with 1N aqueous hydrochloric acidsolution, saturated aqueous sodium bicarbonate solution and saturatedbrine, dried and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:50)to give ((S)-3-bromo-1-bromomethyl-propoxy)-tert-butyldiphenylsilane(8.56 g).

¹H-NMR (CDCl₃) δ: 1.09 (9H, s), 2.16-2.26 (2H, m), 3.27 (2H, d, J=5.0Hz), 3.42 (2H, t, J=7.0 Hz), 4.01-4.06 (1H, m), 7.38-7.50 (6H, m),7.73-7.70 (4H, m).

Step 2

In the same manner as in Steps 4 to 7 of Example 104,[(2S,5S)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en-7-yl]-methanol(0.90 g) was obtained from((S)-3-bromo-1-bromomethyl-propoxy)-tert-butyldiphenylsilane (9.7 g)obtained in the same manner as in Step 1.

¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.18-1.23 (1H, m), 1.35-1.43 (1H, m),1.62-1.85 (8H, m), 1.93-1.98 (2H, m), 3.94 (2H, d, J=4.4 Hz), 4.34 (1H,t t, J=5.1, 5.1 Hz), 5.32 (1H, s), 7.35-7.45 (6H, m), 7.65-7.68 (4H, m).

Step 3

In the same manner as in Steps 8 to 9 of Example 104,(3S)-3-[4-((2S,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (335 mg) was obtained from[(2S,5S)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en-7-yl]-methanol(452 mg) obtained in Step 2.

¹H-NMR (CDCl₃) δ: 1.38-1.78 (9H, m), 1.83 (3H, d, J=2.3 Hz), 1.89 (1H,dd, J=13.8, 5.4 Hz), 1.98-2.07 (3H, m), 2.66 (1H, dd, J=15.1, 7.0 Hz),2.76 (1H, dd, J=15.1, 8.3 Hz), 3.67 (3H, s), 4.03-4.09 (1H, m), 4.32(2H, s), 4.38-4.44 (1H, m), 5.56 (1H, s), 6.86 (2H, d, J=8.6 Hz), 7.27(2H, d, J=8.6 Hz).

Step 4

In the same manner as in Step 9 of Example 1,(3S)-3-[4-((2S,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid (37 mg) was obtained from(3S)-3-[4-((2S,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (77 mg) obtained in Step 3. Configuration of thestructure was determined by NMR spectrum (NOESY, HSQC).

Example 99 Preparation of(3S)-3-[4-((2S,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid sodium salt

In the same manner as in Example 97, the desired compound was obtainedfrom the compound obtained in Example 98.

Example 100 Preparation of(3S)-3-[4-((2R,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid

In the same manner as in Example 106,(3S)-3-[4-((2R,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid (33 mg) was obtained from(3S)-3-[4-((2S,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (65 mg) obtained in the same manner as in step 3 ofExample 98. Configuration of the structure was determined by NMRspectrum (NOESY, HSQC).

Example 101 Preparation of(3S)-3-[4-((2R,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid sodium salt

In the same manner as in Example 97, the desired compound was obtainedfrom the compound obtained in Example 100.

Example 102 Preparation of(3S)-3-[4-((5R)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid

To a solution of(3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (195 mg) obtained in Step 9 of Example 104 inchloroform (2 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Dess-Martin periodinane; 259 mg) under ice-cooling, followed bystirring the mixture under ice-cooling for 3 hours and then at roomtemperature for 1 hour. To the reaction mixture was added aqueous sodiumsulfite solution, followed by extraction with ethyl acetate. The organiclayer was washed successively with saturated aqueous sodium bicarbonatesolution and saturated brine, dried and concentrated. The residue waspurified by column chromatography on silica gel (ethyl acetate:hexane(volume ratio)=1:6 to 1:4) to give(3S)-3-[4-((5R)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (190 mg).

¹H-NMR (DMSO-d₆) δ: 1.43-1.71 (4H, m), 1.77 (3H, d, J=2.3 Hz), 1.79-1.84(2H, m), 1.98-2.07 (3H, m), 2.15-2.26 (3H, m), 2.68 (2H, d, J=7.9 Hz),3.56 (3H, s), 3.94-3.99 (1H, m), 4.36 (2H, s), 5.69 (1H, s), 6.87 (2H,d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz).

Step 2 In the same manner as in Step 9 of Example 1,(3S)-3-[4-((5R)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid (129 mg) was obtained from(3S)-3-[4-((5R)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (190 mg) obtained in Step 1.

Example 103 Preparation of(3S)-3-[4-((5R)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid sodium salt

In the same manner as in Example 97, the desired compound was obtainedfrom the compound obtained in Example 102.

Example 104 Preparation of(3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid

Step 1

To (4R)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (10.27 g) wasadded 2N aqueous hydrochloric acid solution (20 mL), followed bystirring the mixture at room temperature for 5 minutes. The reactionmixture was concentrated and distilled azeotropically with toluene. Theresidue was dissolved in pyridine (40 mL), and to this was addeddropwise methanesulfonyl chloride (10.87 mL) under ice-cooling, followedby stirring the reaction mixture at room temperature for 1 hour. Afteraddition of 2N aqueous hydrochloric acid solution under ice-cooling, thereaction mixture was extracted successively with ethyl acetate twice andwith ethyl acetate:tetrahydrofuran (volume ratio)=1:1 once. The organiclayers were combined, dried and then concentrated. The residue wasrecystallized from ethyl acetate to give methanesulfonic acid(R)-3-hydroxy-4-methanesulfonyloxy-butyl ester (7.88 g).

¹H-NMR (DMSO-d₆) δ: 1.66-1.75 (1H, m), 1.83-1.91 (1H, m), 3.17 (3H, s),3.18 (3H, s), 3.79-3.87 (1H, m), 4.03-4.08 (1H, m), 4.11-4.16 (1H, m),4.27-4.32 (2H, m), 5.35 (1H, brs).

Step 2

To a solution of methanesulfonic acid(R)-3-hydroxy-4-methanesulfonyloxy-butyl ester (7.5 g) obtained in Step1 in N,N-dimethylformamide (30 mL) were added imidazole (2.9 g) andtert-butylchlorodiphenylsilane (10.3 mL) under ice-cooling, followed bystirring the reaction mixture at room temperature for 12 hours. To thereaction mixture was added water under ice-cooling, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane (volumeratio)=1:2 to 1:1) to give methanesulfonic acid(R)-3-(tert-butyldiphenylsilanyloxy)-4-methanesulfonyloxy-b utyl ester(11.4 g).

¹H-NMR (DMSO-d₆) δ: 1.01 (9H, s), 1.91 (2H, dt, J=6.1, 6.1 Hz), 3.00(3H, s), 3.06 (3H, s), 3.99-4.12 (3H, m), 4.15-4.29 (2H, m), 7.41-7.51(6H, m), 7.61-7.66 (4H, m).

Step 3

To a solution of methanesulfonic acid(R)-3-((tert-butyldiphenylsilanyl)-oxy)-4-methanesulfonyloxy-butyl ester(10.9 g) obtained in Step 2 in N,N-dimethylformamide (80 mL) was addedlithium bromide (5.7 g), followed by stirring the mixture at 105° C. for2 hours. To the reaction mixture was added water under ice-cooling,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine, dried and concentrated. The residue was distilledazeotropically with toluene to give((R)-3-bromo-1-bromomethyl-propoxy)-tert-butyldiphenylsilane (10.8 g) asa crude product.

¹H-NMR (CDCl₃) δ: 1.09 (9H, s), 2.16-2.26 (2H, m), 3.27 (2H, d, J=4.9Hz), 3.42 (2H, t, J=7.0 Hz), 4.01-4.06 (1H, m), 7.38-7.49 (6H, m),7.67-7.73 (4H, m).

Step 4

In the same manner as in Steps 1 to 2 of Example 7,(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-oxo-spiro[4.5]decane-7-carboxylic acid methyl ester (1.65 g) as a crude product wasobtained from the crude((R)-3-bromo-1-bromomethyl-propoxy)-tert-butyldiphenylsilane (10.3 g)obtained in Step 3.

¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.47-2.22 (12H, m), 3.67-3.71 (0.5H, m),3.73 (3H, s), 4.44-4.49 (1H, m), 7.35-7.45 (6H, m), 7.62-7.71 (4H, m),12.27 (0.5H, s).

Step 5

To a solution of the crude(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-oxo-spiro[4.5]decane-7-carboxylic acid methyl ester (1.65 g) obtained in Step 4 intoluene (1.6 mL) were added trifluoroacetic acid (5 mL) andtriethylsilane (0.52 mL) under ice-cooling, followed by stirring themixture under ice-cooling for 3 hours. Then, to the reaction mixture wasadded dropwise a solution of potassium carbonate (4.95 g) in water (20mL), and the mixture was stirred under ice-cooling for 10 minutes,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine, dried and concentrated to give(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-hydroxy-spiro[4.5]decane-7-carboxylicacid methyl ester (1.76 g) as a crude product.

¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.21-2.04 (13H, m), 3.50-3.73 (2H, m),3.69 (3H, s), 4.27-4.39 (1H, m), 7.35-7.44 (6H, m), 7.64-7.69 (4H, m).

Step 6

To a solution of the crude(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-6-hydroxy-spiro[4.5]decane-7-carboxylicacid methyl ester (1.76 g) obtained in Step 5 in pyridine (5 mL) wasadded methanesulfonyl chloride (0.25 mL) under ice-cooling, followed bystirring the mixture at room temperature for 15 hours. Then, to thereaction mixture was added water, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried andconcentrated. The residue was dissolved in tetrahydrofuran (10 mL). Tothis solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.88 mL),followed by stirring the mixture at 70° C. for 3.5 hours. After coolingdown to room temperature and adding water, the reaction mixture wasextracted with ethyl acetate. The organic layer was washed successivelywith 1N aqueous hydrochloric acid solution and saturated brine, driedand concentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:30 to 1:25) to give(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-ene-7-carboxylic acid methyl ester (0.615 g).

¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.46-1.54 (1H, m), 1.61-1.85 (8H, m),2.19-2.23 (2H, m), 2.37 (1H, s), 3.70 (3H, s), 4.38 (1H, tt, J=5.8, 3.9Hz), 6.60 (1H, t, J=1.7 Hz), 7.35-7.46 (6H, m), 7.64-7.68 (4H, m).

Step 7

To a solution of(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-ene-7-carboxylic acid methyl ester (615 mg) obtained in Step 6 in toluene(7 mL) was added dropwise sodium bis(2-methoxyethoxy)aluminum hydride(65% toluene solution; 486 mg) under ice-cooling, followed by stirringthe mixture under ice-cooling for 0.5 hour. To the reaction mixture wasadded dropwise 1M aqueous Rochelle salt solution (10 mL), followed bystirring at room temperature for 2 hours, and the reaction mixture wasextracted with toluene. The organic layer was washed with saturatedbrine, dried and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:6 to1:5) to give [(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en-7-yl]-methanol(539 mg).

¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.18-1.23 (1H, m), 1.35-1.43 (1H, m),1.62-1.86 (8H, m), 1.93-1.98 (2H, m), 3.94 (2H, d, J=4.2 Hz), 4.34 (1H,tt, J=5.1, 5.1 Hz), 5.32 (1H, s), 7.35-7.45 (6H, m), 7.65-7.69 (4H, m).

Step 8

In the same manner as in Step 7 of Example 7,(3S)-3-{4-[(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en-7-ylmethoxy]-phenyl}-hex-4-ynoicacid methyl ester (738 mg) was obtained from[(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en-7-yl]-methanol(529 mg) obtained in Step 7.

¹H-NMR (CDCl₃) δ: 1.06 (9H, s), 1.37-1.44 (1H, m), 1.64-1.81 (9H, m),1.83 (3H, d, J=2.6 Hz), 2.00-2.05 (2H, m), 2.65 (1H, dd, J=15.2, 6.8Hz), 2.75 (1H, dd, J=15.2, 8.3 Hz), 3.67 (3H, s), 4.02-4.08 (1H, m),4.28 (2H, s), 4.32-4.37 (1H, m), 5.44 (1H, s), 6.83 (2H, d, J=8.8 Hz),7.25 (2H, d, J=8.8 Hz), 7.35-7.45 (6H, m), 7.65-7.69 (4H, m).

Step 9

To a solution of(3S)-3-{4-[(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en-7-ylmethoxy]-phenyl}-hex-4-ynoicacid methyl ester (738 mg) obtained in step 8 in tetrahydrofuran (3.7mL) was added tetra-n-butylammonium fluoride (1M tetrahydrofuransolution; 2.97 mL), followed by stirring the mixture at room temperaturefor 17 hours. To the reaction mixture was added water, followed byextraction with ethyl acetate. The organic layer was washed withsaturated brine, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane (volumeratio)=1:3) to give(3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (395 mg).

¹H-NMR (DMSO-d₆) δ: 1.34-1.42 (2H, m), 1.47-1.63 (6H, m), 1.65-1.71 (1H,m), 1.77 (3H, d, J=2.6 Hz), 1.80-1.89 (1H, m), 1.92-1.97 (2H, m), 2.68(2H, d, J=7.9 Hz), 3.56 (3H, s), 3.92-4.00 (1H, m), 4.12-4.20 (1H, m),4.31 (2H, s), 4.49 (1H, d, J=3.7 Hz), 5.57 (1H, s), 6.86 (2H, d, J=8.6Hz), 7.24 (2H, d, J=8.6 Hz).

Step 10

In the same manner as in Step 9 of Example 1,(3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid (71 mg) was obtained from(3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (75 mg) obtained in Step 9. Configuration of thestructure was determined by NMR spectrum (NOESY, HSQC).

Example 105 Preparation of(3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid sodium salt

In the same manner as in Example 97, the desired compound was obtainedfrom the compound obtained in Example 104.

Example 106 Preparation of(3S)-3-[4-((2S,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid

Step 1

To a solution of(3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (133 mg) obtained in the same manner as in Step 9 ofExample 104 in tetrahydrofuran (1.5 mL) were added successivelytriphenylphosphine (119 mg), acetic acid (0.03 mL) and dimethylazodicarboxylate (0.168 mL) under ice-cooling, followed by stirring themixture at room temperature for 16 hours. The reaction mixture wasconcentrated and the residue was purified by thin-layer columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:5)to give(3S)-3-[4-((2S,5R)-2-acetoxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (107 mg).

¹H-NMR (DMSO-d₆) δ: 1.41-1.70 (8H, m), 1.77 (3H, d, J=2.6 Hz), 1.84-1.91(1H, m), 1.94-1.98 (5H, m), 1.99-2.07 (1H, m), 2.68 (2H, d, J=7.9 Hz),3.56 (3H, s), 3.93-4.00 (1H, m), 4.34 (2H, s), 5.04-5.10 (1H, m), 5.66(1H, s), 6.87 (2H, d, J=8.6 Hz), 7.24 (2H, d, J=8.6 Hz).

Step 2

To a solution of(3S)-3-[4-((2S,5R)-2-acetoxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid methyl ester (107 mg) obtained in Step 1 in a mixed solvent ofmethanol (0.65 mL)-tetrahydrofuran (0.65 mL) was added 2N aqueous sodiumhydroxide solution (0.28 mL) under ice-cooling, followed by stirring themixture at room temperature overnight. To the reaction mixture was added2N aqueous hydrochloric acid solution (0.28 mL), followed by extractionwith ethyl acetate. The organic layer was washed with saturated brine,dried and concentrated. The residue was purified by thin-layer columnchromatography on silica gel (acetic acid:methanol:chloroform (volumeratio)=0.1:1:20) to give(3S)-3-[4-((2S,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid (79 mg). Configuration of the structure was determined by NMRspectrum (NOESY, HSQC).

Example 107 Preparation of(3S)-3-[4-((2S,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoicacid sodium salt

In the same manner as in Example 97, the desired compound was obtainedfrom the compound obtained in Example 106.

Example 108 Preparation of3-[2-chloro-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-prop ionic acid

In the same manner as in Steps 2 and 4 to 6 of Example 110,3-[2-chloro-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-prop ionic acid(75 mg) was obtained from 2-chloro-4-hydroxybenzaldehyde (250 mg).

Example 109 Preparation of3-[2-methyl-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-prop ionic acid

In the same manner as in Steps 2 and 4 to 6 of Example 110,3-[2-methyl-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-prop ionic acid(107 mg) was obtained from 4-hydroxy-2-methylbenzaldehyde (507 mg).

Example 110 Preparation of3-[3-hydroxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acid

Step 1

To a solution of 3,4-dihydroxybenzaldehyde (5.0 g) inN,N-dimethylformamide (36 mL) was added 60% sodium hydride (1.45 g)under ice-cooling, followed by stirring the reaction mixture at roomtemperature for 10 minutes. Then, after addition of acetic anhydride(3.6 mL), the reaction mixture was stirred at room temperature for 1hour. To the reaction mixture was added 2N aqueous hydrochloric acidsolution under ice-cooling, followed by extraction with ethyl acetate.The organic layer was washed with saturated aqueous sodium bicarbonatesolution and saturated brine, dried and concentrated. The residue waspurified by column chromatography on silica gel (ethyl acetate:hexane(volume ratio)=1:2 to 1:1) to give acetic acid 5-formyl-2-hydroxyphenylester (4.9 g).

¹H-NMR (acetone-d₆) δ: 2.29 (3H, s), 7.13 (1H, d, J=8.4 Hz), 7.61 (1H,d, J=2.1 Hz), 7.70 (1H, dd, J=8.4, 2.1 Hz), 9.35 (1H, brs), 9.85 (1H,s).

Step 2

To a solution of acetic acid 5-formyl-2-hydroxyphenyl ester (2.1 g)obtained in Step 1 in tetrahydrofuran (20 mL) were added successivelytriphenylphosphine (4.3 g), spiro[4.5]dec-6-ene-7-methanol (3.55 g)obtained in the same manner as in Step 6 of Example 7 and1,1′-azobis(N,N-dimethylformamide) (2.8 g) under ice-cooling, followedby stirring the reaction mixture at room temperature for 1.5 hours.After addition of diethyl ether to the reaction mixture, the insolubleswere filtered off and the filtrate was concentrated. The residue waspurified by column chromatography on silica gel (ethyl acetate:hexane(volume ratio)=1:9 to 1:6) to give a mixture (1.8 g) of acetic acid5-formyl-2-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl ester and3-hydroxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-benzaldehyde.

¹H-NMR (3-hydroxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-benzaldehyde,CDCl₃) δ: 1.45-1.50 (6H, m), 1.63-1.70 (6H, m), 2.04 (2H, t, J=5.7 Hz),4.54 (2H, s), 5.64 (1H, s), 5.79 (1H, s), 6.98 (1H, d, J=8.4 Hz), 7.41(1H, dd, J=8.4, 2.0 Hz), 7.45 (1H, d, J=2.0 Hz), 9.85 (1H, s).

Step 3

To a solution of a mixture (1.7 g) of acetic acid5-formyl-2-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl ester and3-hydroxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-benzaldehyde obtained inStep 2 in chloroform (9 mL) were added triethylamine (1.7 mL) and acetylchloride (0.4 mL) under ice-cooling, followed by stirring the reactionmixture under ice-cooing for 1 hour. After addition of saturated aqueoussodium bicarbonate solution, the reaction mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, driedand concentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:19 to 1:9) to giveacetic acid 5-formyl-2-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl ester(1.59 g).

¹H-NMR (CDCl₃) δ: 1.46-1.49 (6H, m), 1.63-1.71 (6H, m), 1.99 (2H, t,J=5.7 Hz), 2.33 (3H, s), 4.48 (2H, s), 5.61 (1H, s), 7.08 (1H, d, J=8.6Hz), 7.59 (1H, d, J=2.1 Hz), 7.73 (1H, dd, J=8.5, 2.1 Hz), 9.87 (1H, s).

Step 4

To a solution of 60% sodium hydride (0.118 g) in tetrahydrofuran (11.5mL) was added triethyl phosphonoacetate (0.64 mL) under argon atmosphereand ice-cooling, followed by stirring under ice-cooling for 10 minutes.To this mixture was added a solution of acetic acid5-formyl-2-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl ester (0.75 g)obtained in Step 3 in tetrahydrofuran (3.8 mL), followed by stirring atroom temperature for 10 minutes. After addition of ice-cold water, thereaction mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, dried and concentrated. The residue waspurified by column chromatography on silica gel (hexane→ethylacetate:hexane (volume ratio)=1:19 to 1:9) to give(E)-3-[3-acetoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-acrylic acidethyl ester (0.9 g).

¹H-NMR (CDCl₃) δ: 1.28-1.38 (3H, m), 1.43-1.53 (6H, m), 1.60-1.69 (6H,m), 1.99 (2H, t, J=6.0 Hz), 2.32 (3H, s), 4.26 (2H, q, J=7.2 Hz), 4.42(2H, s), 5.58 (1H, s), 6.29 (1H, d, J=16.0 Hz), 6.96 (1H, d, J=8.6 Hz),7.24 (1H, d, J=2.1 Hz), 7.34 (1H, dd, J=8.6, 2.1 Hz), 7.60 (1H, d,J=16.0 Hz).

Step 5

To a solution of(E)-3-[3-acetoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-acrylic acidethyl ester (0.43 g) obtained in Step 4 in ethyl acetate (8 mL) wereadded 10% palladium carbon (86 mg) and a 0.1M ethyl acetate solution ofdiphenyl sulfide (1.08 mL), followed by stirring under increasedpressure (0.4 MPa) in an atmosphere of hydrogen at room temperature for6 hours. The reaction mixture was filtered through Celite and thefiltrate was concentrated. The residue was purified by columnchromatography on silica gel (hexane→ethyl acetate:hexane (volumeratio)=1:19 to 1:9) to give3-[3-acetoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acidethyl ester (0.332 g).

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J=7.2 Hz), 1.44-1.51 (6H, m), 1.62-1.68(6H, m), 1.99 (2H, t, J=5.8 Hz), 2.30 (3H, s), 2.59 (2H, t, J=7.8 Hz),2.89 (2H, t, J=7.8 Hz), 4.13 (2H, q, J=7.1 Hz), 4.35 (2H, s), 5.56 (1H,s), 6.89 (2H, t, J=4.1 Hz), 7.00 (1H, dd, J=8.4, 2.1 Hz).

Step 6

In the same manner as in Step 9 of Example 1,3-[3-hydroxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acid(51 mg) was obtained from3-[3-acetoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acidethyl ester (100 mg) obtained in Step 5.

Example 111 Preparation of3-[3-methoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acid

Step 1

To a solution of3-[3-hydroxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acid(188 mg) obtained in the same manner as in Example 110 inN,N-dimethylformamide (2 mL) were added methyl iodide (0.082 mL) andpotassium carbonate (0.30 mg), followed by stirring the mixture at roomtemperature for 16 hours. To the reaction mixture was added 1N aqueoushydrochloric acid solution, followed by extraction with ethyl acetate.The organic layer was washed with water and saturated brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:40 to 1:10) to give3-[3-methoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acidmethyl ester (176 mg).

¹H-NMR (CDCl₃) δ: 1.43-1.47 (6H, m), 1.61-1.68 (6H, m), 2.04-2.09 (2H,m), 2.60-2.64 (2H, m), 2.90 (2H, t, J=7.9 Hz), 3.68 (3H, s), 3.85 (3H,s), 4.42 (2H, s), 5.56 (1H, s), 6.69 (1H, dd, J=8.1, 2.1 Hz), 6.72 (1H,d, J=2.1 Hz), 6.82 (1H, d, J=8.1 Hz).

Step 2

3-[3-Methoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acidmethyl ester (176 mg) obtained in Step 1 was subjected to the reactionin the same condition as in Step 9 of Example 1 to give3-[3-methoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acid(159 mg).

Example 112 Preparation of3-[3-fluoro-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acid

In the same manner as in Steps 2 and 4 to 6 of Example 110,3-[3-fluoro-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-prop ionic acid(80 mg) was obtained from 3-fluoro-4-hydroxybenzaldehyde (500 mg).

Example 113 Preparation of3-[6-(spiro[4.5]dec-7-ylmethoxy)-pyridin-3-yl]-propionic acidhydrochloride

Step 1

To a solution of spiro[4.5]dec-6-ene-7-carboxylic acid methyl ester (4.5g) obtained in the same manner as in Step 5 of Example 7 intetrahydrofuran (45 mL) was added 5% palladium carbon (0.5 g), followedby stirring under increased pressure (0.4 MPa) in an atmosphere ofhydrogen at room temperature for 17 hours. The reaction mixture wasfiltered through Celite and the filtrate was washed with tetrahydrofuran(50 mL). To this solution was added dropwise a 1M toluene solution ofdiisobutylaluminum hydride (70 mL) under argon atmosphere at −70° C.,followed by raising the temperature to −20° C. over 1.5 hours whilestirring the reaction mixture. 2N aqueous hydrochloric acid solution wasadded to the reaction mixture and the temperature was raised to roomtemperature, followed by extraction with ethyl acetate. The organiclayer was washed with saturated brine, dried and concentrated. Theresidue was purified by column chromatography on silica gel(hexane→ethyl acetate:hexane (volume ratio)=1:9) to givespiro[4.5]dec-7-yl-methanol (3.6 g).

¹H-NMR (CDCl₃) δ: 0.84 (1H, qd, J=12.6, 4.2 Hz), 0.92 (1H, t, J=12.6Hz), 1.15 (1H, td, J=12.6, 4.2 Hz), 1.27 (1H, t, J=4.2 Hz), 1.31-1.67(13H, m), 1.71-1.78 (1H, m), 3.42 (2H, t, J=6.0 Hz).

Step 2

To a mixture of palladium(II) acetate (135 mg),2-(di-tert-butylphosphino)-1,1′-binaphthyl (478 mg) and cesium carbonate(3.9 g) was added toluene (15 mL), followed by stirring under argonatmosphere at room temperature for 10 minutes. To this reaction mixturewere added spiro[4.5]dec-7-yl-methanol (1.0 g) obtained in Step 1 and6-bromopyridine-3-carboxaldehyde (1.1 g), followed by stirring themixture at 90° C. for 1.5 hours. The reaction mixture was filteredthrough Celite and the filtrate was concentrated. The residue waspurified by column chromatography on silica gel (ethyl acetate:hexane(volume ratio) 1:49 to 1:9) to give6-(spiro[4.5]dec-7-ylmethoxy)-pyridine-3-carboxaldehyde (0.313 g).

¹H-NMR (CDCl₃) δ: 0.95-1.23 (4H, m), 1.32-1.52 (4H, m), 1.55-1.68 (9H,m), 1.82-1.97 (2H, m), 4.19 (2H, d, J=6.4 Hz), 6.83 (1H, d, J=8.6 Hz),8.05 (1H, dd, J=8.6, 2.4 Hz), 8.60 (1H, dd, J=2.3, 0.6 Hz), 9.94 (1H, d,J=0.6 Hz).

Step 3

6-(Spiro[4.5]dec-7-ylmethoxy)-pyridine-3-carboxaldehyde (0.313 g)obtained in Step 2 was subjected to the reaction in the same conditionas in Steps 4 and 5 of Example 110 to give3-[6-(spiro[4.5]dec-7-ylmethoxy)-pyridin-3-yl]-propionic acid ethylester (36 mg).

¹H-NMR (CDCl₃) δ: 0.90-1.08 (4H, m), 1.15-1.31 (3H, m), 1.38-1.50 (7H,m), 1.56-1.67 (9H, m), 1.83-1.93 (2H, m), 2.58 (2H, t, J=7.7 Hz), 2.87(2H, t, J=7.7 Hz), 4.03 (2H, d, J=6.3 Hz), 4.13 (2H, q, J=7.2 Hz), 6.67(1H, d, J=8.6 Hz), 7.42 (1H, dd, J=8.6, 2.5 Hz), 7.98 (1H, d, J=2.4 Hz).

Step 4

To a solution of3-[6-(spiro[4.5]dec-7-ylmethoxy)-pyridin-3-yl]-propionic acid ethylester (36 mg) obtained in Step 3 in a mixed solvent of tetrahydrofuran(0.36 mL)-ethanol (0.36 mL) was added 1N aqueous sodium hydroxidesolution (0.21 mL), followed by stirring the reaction mixture at roomtemperature for 1.5 hours. Then, to the reaction mixture was added 1Naqueous hydrochloric acid solution, followed by extraction with ethylacetate. The organic layer was washed with saturated brine, dried andconcentrated. The residue was dissolved in a 1,4-dioxane solution ofhydrogen chloride (4M, 0.5 mL), and to this was added hexane (0.5 mL)while stirring. The resulting solid was filtered and then dried to give3-[6-(spiro[4.5]dec-7-ylmethoxy)-pyridin-3-yl]-propionic acidhydrochloride (33 mg).

Example 114 Preparation of3-[4-(9-methoxy-spiro[5.5]undec-3-ylmethoxy)-phenyl]-propionic acid

Step 1

To a solution of cyclohexane-1,4-dimethanol (10.0 g) inN,N-dimethylformamide (100 mL) were added successivelytert-butyldimethylchlorosilane (8.9 g) and imidazole (9.5 g), followedby stirring the reaction mixture at room temperature for 16 hours. Tothe reaction mixture were added ice and saturated aqueous lithiumbromide solution, followed by extraction with diethyl ether. The organiclayer was washed with saturated aqueous lithium bromide solution andsaturated brine, dried and concentrated. The residue was purified bycolumn chromatography on silica gel (ethyl acetate:hexane (volumeratio)=1:9 to 2:3) to give[4-(tert-butyldimethylsilanyloxymethyl)-cyclohexyl]-methanol (8.7 g).

¹H-NMR (CDCl₃) δ: 0.04 (6H, s), 0.85-1.05 (3H, m), 0.89 (9H, s),1.21-1.31 (2H, m), 1.33-1.56 (3.4H, m), 1.61-1.72 (0.6H, m), 1.82 (2H,d, J=1.4 Hz), 3.41 (1.4H, d, J=6.7 Hz), 3.47 (2H, q, J=6.3 Hz), 3.55(0.6H, dd, J=6.7, 5.8 Hz).

Step 2

To a solution of[4-(tert-butyldimethylsilanyloxymethyl)-cyclohexyl]-methano 1 (8.5 g)obtained in Step 1 in chloroform (85 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one(Dess-Martin periodinane; 15.3 g) under ice-cooling, followed bystirring the mixture under ice-cooling for 2.5 hours. After addition ofaqueous sodium sulfite solution and aqueous sodium bicarbonate solution,the reaction mixture was filtered through Celite, followed by extractionwith ethyl acetate. The organic layer was washed with saturated brine,dried and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:19to 1:9) to give4-(tert-butyldimethylsilanyloxymethyl)-cyclohexanecarbaldehyde (6.9 g).

¹H-NMR (CDCl₃) δ: 0.06 (6H, s), 0.85-0.93 (9H, m), 0.93-1.09 (2H, m),1.23-1.33 (1H, m), 1.40-1.69 (3H, m), 1.88-1.92 (2H, m), 2.00-2.04 (1H,m), 2.09-2.22 (1H, m), 3.38-3.44 (2H, m), 9.63 (0.5H, d, J=1.6 Hz), 9.71(0.5H, s).

Step 3

In the same manner as in Steps 1 to 2 of Example 1,9-(tert-butyldimethylsilanyloxymethyl)-spiro[5.5]undecan-3-one (1.5 g)was obtained from4-(tert-butyldimethylsilanyloxymethyl)-cyclohexanecarbaldehyde (1.16 g)obtained in Step 2.

¹H-NMR (CDCl₃) δ: 0.04 (6H, s), 0.90 (9H, s), 1.12 (2H, qd, J=12.8, 3.4Hz), 1.25 (2H, td, J=12.8, 3.4 Hz), 1.43-1.54 (1H, m), 1.61-1.67 (4H,m), 1.73-1.79 (4H, m), 2.28 (2H, t, J=7.0 Hz), 2.35 (2H, t, J=7.0 Hz),3.45 (2H, d, J=6.3 Hz).

Step 4

To a solution of9-(tert-butyldimethylsilanyloxymethyl)-spiro[5.5]undecan-3-one (1.5 g)obtained in Step 3 in methanol (24 mL) was added sodium borohydride(0.17 g) under ice-cooling, followed by stirring the reaction mixtureunder ice-cooling for 0.5 hour. After addition of saturated aqueouscitric acid solution, the reaction mixture was concentrated in vacuo,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine, dried and concentrated. The residue was purifiedby column chromatography on silica gel (ethyl acetate:hexane (volumeratio)=1:19 to 1:4) to give9-(tert-butyldimethylsilanyloxymethyl)-spiro[5.5]undecan-3-ol (0.47 g).

¹H-NMR (CDCl₃) δ: 0.01 (6H, s), 0.84 (9H, s), 0.87-1.21 (7H, m),1.29-1.55 (5H, m), 1.65-1.73 (3H, m), 1.80-1.90 (2H, m), 3.38 (2H, d,J=6.2 Hz), 3.57-3.61 (1H, m).

Step 5

To a solution of9-(tert-butyldimethylsilanyloxymethyl)-spiro[5.5]undecan-3-ol (309 mg)obtained in Step 4 in N,N-dimethylformamide (5 mL) was added 60% sodiumhydride (60 mg) under ice-cooling, followed by stirring the reactionmixture at room temperature for 5 minutes. To the reaction mixture wasadded iodomethane (0.19 mL), followed by stirring at room temperaturefor 15 minutes. To the reaction mixture were further added 60% sodiumhydride (120 mg) and iodomethane (0.38 mL), followed by stirring at roomtemperature for 15 minutes. To the reaction mixture was added 1N aqueoushydrochloric acid solution under ice-cooling, followed by extractionwith diethyl ether three times. The organic layer was dried and thenconcentrated to givetert-butyl-(9-methoxyspiro[5.5]undec-3-ylmethoxy)-dimethylsilane (393mg) as a crude product.

¹H-NMR (CDCl₃) δ: 0.04 (6H, s), 0.90 (9H, s), 0.95-1.20 (8H, m),1.27-1.58 (4H, m), 1.72-1.87 (5H, m), 3.12-3.18 (1H, m), 3.34 (3H, s),3.42 (2H, d, J=6.5 Hz).

Step 6

To a solution of the crudetert-butyl-(9-methoxyspiro[5.5]undec-3-ylmethoxy)-dimethylsilane (393mg) obtained in Step 5 in tetrahydrofuran (5 mL) was added a 1Mtetrahydrofuran solution of tetra-n-butylammonium fluoride (3 mL) underice-cooling, followed by stirring the reaction mixture at roomtemperature for 1.5 hours. To the reaction mixture was added water,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine, dried and concentrated. The residue was purifiedby column chromatography on silica gel (ethyl acetate:hexane (volumeratio)=1:19 to 1:4) to give (9-methoxyspiro[5.5]undec-3-yl) methanol(217 mg).

¹H-NMR (CDCl₃) δ: 0.94-1.51 (4H, m), 1.56 (4H, m), 1.70-1.89 (7H, m),3.12-3.18 (1H, m), 3.33 (3H, s), 3.47 (2H, d, J=6.0 Hz).

Step 7

In the same manner as in Steps 8 to 9 of Example 21,3-[4-(9-methoxy-spiro[5.5]undec-3-ylmethoxy)-phenyl]-propionic acid (109mg) was obtained from (9-methoxyspiro[5.5]undec-3-yl)methanol (208 mg)obtained in Step 6.

Example 115 Preparation of3-[4-(9,9-dimethyl-spiro[4.5]dec-7-ylmethoxy)-phenyl]-propionic acid

Step 1

In the same manner as in Steps 1 to 2 of Example 7,9,9-dimethyl-6-oxo-spiro[4.5]decane-7-carboxylic acid methyl ester (461mg) was obtained from 4,4-dimethylcyclohexanone (800 mg).

¹H-NMR (CDCl₃) δ: 0.96 (4.2H, s), 1.02 (0.9H, s), 1.21 (0.9H, s),1.49-1.89 (8H, m), 2.01-2.07 (4H, m), 3.74 (3H, s), 3.78 (0.3H, dd,J=13.9, 5.3 Hz), 12.46 (0.7H, s).

Step 2

To a solution of 9,9-dimethyl-6-oxo-spiro[4.5]decane-7-carboxylic acidmethyl ester (450 mg) obtained in Step 1 in methanol (4.5 mL) was addedcalcium chloride dihydrate (417 mg), followed by stirring underice-cooling for 15 minutes. Then, to the reaction mixture was addedsodium borohydride (90 mg) in three portions, followed by stirring thereaction mixture under ice-cooling for 1.5 hours. To the reactionmixture were added successively 2N aqueous hydrochloric acid solution,toluene and saturated brine, and the mixture was stirred for 5 minutes,followed by separation of the aqueous layer. The organic layer waswashed successively with water and saturated brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:hexane (volume ratio)=1:19 to 1:6) to give6-hydroxy-9,9-dimethyl-spiro[4.5]decane-7-carboxylic acid methyl ester(341 mg).

¹H-NMR (CDCl₃) δ: 0.91-1.02 (6H, m), 1.18-1.72 (8H, m), 1.73-2.01 (4H,m), 2.44 (0.6H, d, J=4.4 Hz), 2.63 (0.6H, ddd, J=13.6, 10.1, 3.0 Hz),2.76 (0.4H, dq, J=13.5, 1.8 Hz), 2.89 (0.4H, d, J=2.6 Hz), 3.62 (0.6H,dd, J=10.6, 4.1 Hz), 3.69 (0.4H, s), 3.72 (3H, s).

Step 3

In the same manner as in Step 6 of Example 104,(9,9-dimethyl-spiro[4.5]dec-6-en-7-yl)-methanol (243 mg) was obtainedfrom 6-hydroxy-9,9-dimethyl-spiro[4.5]decane-7-carboxylic acid methylester (330 mg) obtained in Step 2.

¹H-NMR (CDCl₃) δ: 0.96 (6H, s), 1.49-1.54 (4H, m), 1.56 (2H, s),1.62-1.70 (4H, m), 1.78 (2H, s), 3.99 (2H, d, J=4.9 Hz), 5.50 (1H, s).

Step 4

In the same manner as in Step 5 of Example 22,(9,9-dimethyl-spiro[4.5]dec-7-yl)-methanol (169 mg) was obtained from(9,9-dimethyl-spiro[4.5]dec-6-en-7-yl)-methanol (199 mg) obtained inStep 3.

¹H-NMR (CDCl₃) δ: 0.90 (3H, s), 0.96 (3H, s), 1.23-1.57 (10H, m),1.57-1.69 (4H, m), 1.69-1.81 (1H, m), 3.45 (2H, d, J=4.4 Hz).

Step 5

In the same manner as in Steps of 8 to 9 of Example 21,3-[4-(9,9-dimethyl-spiro[4.5]dec-7-ylmethoxy)-phenyl]-propionic acid(129 mg) was obtained from (9,9-dimethyl-spiro[4.5]dec-7-yl)-methanol(100 mg) obtained in Step 4.

Example 116 Preparation of(3S)-3-[4-(spiro[2.6]non-5-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

To a suspension of potassium tert-butoxide (3.48 g) in tert-butanol (32mL) was added cycloheptanone (1.9 mL) while stirring under nitrogenatmosphere, followed by stirring the mixture at room temperature for 0.5hour. Then, to the reaction mixture was added(2-chloroethyl)-dimethylsulfonium iodide (3.7 g) in eight portions over1.6 hours, followed by stirring the mixture at room temperature for 16.5hours. To the reaction mixture was added water, followed by extractionwith diethyl ether. The organic layer was washed with saturated brine,dried and concentrated. The residue was purified by columnchromatography on silica gel (diethyl ether:hexane (volume ratio)=1:15)to give spiro[2.6]nonan-4-one (1.40 g).

¹H-NMR (CDCl₃) δ: 0.67 (2H, ddd, J=3.4, 3.4, 3.4 Hz), 1.24 (2H, ddd,J=3.4, 3.4, 3.4 Hz), 1.66-1.73 (6H, m), 1.73-1.78 (2H, m), 2.63-2.66(2H, m).

Step 2

In the same manner as in Step 2 of Example 7 and Step 2 of Example 115,4-hydroxy-spiro[2.6]nonane-5-carboxylic acid methyl ester (1.47 g) wasobtained from spiro[2.6]nonan-4-one (1.40 g) obtained in Step 1.

¹H-NMR (CDCl₃) δ: 0.31-0.44 (3H, m), 0.57-0.63 (1H, m), 0.74-0.80 (1H,m), 1.55-1.71 (3H, m), 1.77-1.84 (2H, m), 2.08-2.25 (2H, m), 2.66 (1H,dt, J=11.1, 2.2 Hz), 2.71 (1H, d, J=2.2 Hz), 3.22 (1H, s), 3.69 (3H, s).

Step 3

To a solution of 4-hydroxy-spiro[2.6]nonane-5-carboxylic acid methylester (0.899 g) obtained in Step 2 in chloroform (18 mL) were addedsuccessively triethylamine (6.33 mL), 4-dimethylaminopyridine (0.11 g)and acetic anhydride (2.15 mL) under argon atmosphere and ice-cooling,followed by stirring the mixture at room temperature for 3.5 hours.After ice-cooling the reaction mixture and adding saturated aqueoussodium bicarbonate solution thereto, the reaction mixture was extractedwith ethyl acetate. The organic layer was washed successively withsaturated aqueous sodium bicarbonate solution and saturated brine, driedand concentrated. The residue was purified by column chromatography onsilica gel (diethyl ether:hexane (volume ratio)=1:9) to give4-acetoxy-spiro[2.6]nonane-5-carboxylic acid methyl ester (1.06 g).

¹H-NMR (CDCl₃) δ: 0.35-0.40 (1H, m), 0.43-0.48 (1H, m), 0.50-0.55 (1H,m), 0.72-0.77 (1H, m), 0.82-0.89 (1H, m), 1.55-1.74 (3H, m), 1.77-1.85(1H, m), 1.87-1.95 (1H, m), 1.97-2.15 (2H, m), 2.07 (3H, s), 2.78 (1H,dq, J=11.2, 1.8 Hz), 3.63 (3H, s), 4.64 (1H, t, J=0.9 Hz).

Step 4

To a solution of 4-acetoxy-spiro[2.6]nonane-5-carboxylic acid methylester (1.06 g) obtained in Step 3 in toluene (11 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (3.3 mL), followed by stirring thereaction mixture at 120° C. for 5.5 hours. After ice-cooling thereaction mixture, water (25 mL) and 1N aqueous hydrochloric acidsolution (25 mL) were added thereto, followed by extraction with ethylacetate. The organic layer was washed successively with saturatedaqueous sodium bicarbonate solution and saturated brine, dried andconcentrated. The residue was purified by column chromatography onsilica gel (diethyl ether:hexane (volume ratio)=1:20) to givespiro[2.6]non-4-en-5-yl-methanol (0.32 g).

¹H-NMR (CDCl₃) δ: 0.49-0.57 (4H, m), 1.27 (1H, brs), 1.46 (2H, t, J=5.7Hz), 1.65-1.75 (4H, m), 2.22 (2H, dd, J=6.8, 4.1 Hz), 3.95 (2H, s), 5.24(1H, s).

Step 5

To a solution of spiro[2.6]non-4-en-5-yl-methanol (170 mg) obtained inStep 4 in ethanol (3.4 mL) was added platinum oxide (35 mg), followed bystirring the reaction mixture at room temperature under normal pressurein an atmosphere of hydrogen for 2 hours. Then, the reaction mixture wasfiltered through Celite. The filtrate was concentrated and the residuewas purified by column chromatography on silica gel (ethylacetate:hexane (volume ratio)=1:7) to give spiro[2.6]non-5-yl-methanol(164 mg).

¹H-NMR (CDCl₃) δ: 0.23-0.36 (3.6H, m), 0.86-0.93 (0.4H, m), 1.12-1.37(4H, m), 1.44-1.83 (7H, m), 3.35-3.44 (2H, m).

Step 6

In the same manner as in Steps 8 to 9 of Example 1,(3S)-3-[4-(spiro[2.6]non-5-ylmethoxy)-phenyl]-hex-4-ynoic acid (157 mg)was obtained from spiro[2.6]non-5-yl-methanol (100 mg) obtained in Step5.

Example 117 Preparation of3-[4-(spiro[3.4]oct-5-en-6-ylmethoxy)-phenyl]-propionic acid

Step 1

To a solution of lithium chloride (2.12 g) in tetrahydrofuran (60 mL)was added samarium (II) iodide (5.0 g) under argon atmosphere, followedby stirring the mixture at room temperature for 15 minutes. To thisreaction mixture was added dropwise a solution of cyclobutanone (825 mg)in tetrahydrofuran (5 mL), followed by stirring the mixture at roomtemperature for 1 hour. To the reaction mixture was added saturatedaqueous sodium thiosulfate solution under ice-cooling, followed byextraction with diethyl ether three times. The organic layers werecombined, washed with saturated brine, dried and concentrated. Theresidue was purified by column chromatography on silica gel (ethylacetate:hexane (volume ratio)=1:19 to 3:2) to givebicyclobutyl-1,1′-diol (399 mg).

¹H-NMR (CDCl₃) δ: 1.58-1.71 (2H, m), 1.93-2.07 (6H, m), 2.15 (2H, s),2.27-2.37 (4H, m).

Step 2

To bicyclobutyl-1,1′-diol (1.95 g) obtained in the same manner as inStep 1 was added 10% aqueous sulfuric acid solution (20 mL), followed bystirring the mixture at 90° C. for 3 hours.

The reaction mixture was ice-cooled and extracted with diethyl ether.The organic layer was washed successively with water and saturatedbrine, dried and concentrated. The residue was purified by columnchromatography on silica gel (hexane→diethyl ether:hexane (volumeratio)=1:6) to give spiro[3.4]octan-5-one (583 mg).

¹H-NMR (CDCl₃) δ: 1.77-1.86 (4H, m), 1.90-2.03 (4H, m), 2.17 (2H, t,J=7.6 Hz), 2.23-2.30 (2H, m).

Step 3

In the same manner as in Steps 2 to 4 of Example 116,spiro[3.4]oct-5-en-6-yl-methanol (116 mg) was obtained fromspiro[3.4]octan-5-one (545 mg) obtained in Step 2.

¹H-NMR (CDCl₃) δ: 1.77-1.90 (2H, m), 1.92-2.10 (6H, m), 2.30 (2H, t,J=7.0 Hz), 4.17 (2H, s), 5.73 (1H, s).

Step 4

In the same manner as in Steps 8 to 9 of Example 21,3-[4-(spiro[3.4]oct-5-en-6-ylmethoxy)-phenyl]-propionic acid (108 mg)was obtained from spiro[3.4]oct-5-en-6-yl-methanol (58 mg) obtained inStep 3.

Example 118 Preparation of(3S)-3-[4-(spiro[3.4]oct-6-ylmethoxy)-phenyl]-hex-4-ynoic acid

Step 1

In the same manner as in Step 5 of Example 116,spiro[3.4]oct-6-yl-methanol (53 mg) was obtained fromspiro[3.4]oct-5-en-6-yl-methanol (50 mg) obtained in Step 3 of Example117.

¹H-NMR (CDCl₃) δ: 1.24-1.32 (3H, m), 1.63 (2H, t, J=7.2 Hz), 1.70-1.79(1H, m), 1.79-1.91 (7H, m), 2.08-2.20 (1H, m), 3.49 (2H, d, J=7.2 Hz).

Step 2

In the same manner as in Steps 8 to 9 of Example 1,(3S)-3-[4-(spiro[3.4]oct-6-ylmethoxy)-phenyl]-hex-4-ynoic acid (88 mg)was obtained from spiro[3.4]oct-6-yl-methanol (50 mg) obtained in Step1.

Example 119 Preparation of(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidL-lysine salt

To a solution of(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid (50mg) obtained in the same manner as in Example 1 in a mixed solvent ofN,N-dimethylformamide (0.75 mL)-water (0.059 mL) was added 50% aqueousL-lysine solution (0.032 mL) at 50° C., followed by stirring overnightwhile gradually cooling the mixture down to room temperature. Theprecipitate was filtered and then dried to give(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acidL-lysine salt (45 mg).

Example 120 Preparation of(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionicacid L-lysine salt

To a solution of(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionicacid (50 mg) obtained in the same manner as in Example 42 in a mixedsolvent of N,N-dimethylformamide (0.75 mL)-water (0.044 mL) was added50% aqueous L-lysine solution (0.032 mL) at 50° C., followed by stirringovernight while gradually cooling the mixture down to room temperature.The precipitate was filtered and then dried to give(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionicacid L-lysine salt (52 mg).

The structural formulae of the compounds obtained in Examples 1 to 120are shown in Tables 1 to 17. In Tables 1 to 17, the chirality of thecarbon atom in a methine group substituted by a phenyl group or apyridyl group is represented as “the chirality at the benzylic carbon”.

With regard to the compounds obtained in Examples 1 to 120, the compoundnames and NMR data are shown in Tables 18 to 26 and in Tables 27 to 38,respectively.

TABLE 1 Chirality Chirality of Other Ex. at benzylic carbon at chiralNo. Structural formula carbon spiro junction carbon 1

S-isomer — — 2

S-isomer — — 3

S-isomer — — 4

S-isomer — — 5

S-isomer — — 6

S-isomer — — 7

S-isomer — —

TABLE 2 Chirality Chirality of Other Ex. at benzylic carbon at chiralNo. Structural formula carbon spiro junction carbon 8

S-isomer — — 9

S-isomer — — 10

S-isomer — — 11

S-isomer — — 12

S-isomer — — 13

S-isomer — — 14

S-isomer — —

TABLE 3 Chirality at Chirality of Other Ex. benzylic carbon at chiralNo. Structural formula carbon spiro junction carbon 15

S-isomer — — 16

S-isomer — — 17

S-isomer — — 18

S-isomer — — 19

S-isomer racemate spiro-C6: racemate 20

S-isomer racemate spiro-C6: racemate 21

— racemate —

TABLE 4 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 22

S-isomer — — 23

S-isomer — — 24

S-isomer — — 25

S-isomer — — 26

S-isomer racemate — 27

S-isomer racemate — 28

S-isomer racemate —

TABLE 5 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 29

S-isomer racemate — 30

S-isomer racemate — 31

S-isomer racemate — 32

S-isomer chiral: A — 33

S-isomer chiral: A — 34

S-isomer chiral: B — 35

S-isomer chiral: B —

TABLE 6 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 36

S-isomer chiral: A — 37

S-isomer chiral: A 38

S-isomer chiral: B — 39

S-isomer chiral: B — 40

racemate racemate — 41

racemate — — 42

(−)-isomer — —

TABLE 7 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 43

(−)-isomer — — 44

(+)-isomer — — 45

racemate — — 46

— racemate — 47

racemate racemate — 48

— racemate spiro-C6: racemate 49

— racemate —

TABLE 8 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 50

— racemate spiro-C6 C11: racemate 51

— racemate spiro-C7, C11: racemate 52

— racemate — 53

— racemate spiro-C6: racemate 54

— racemate — 55

— racemate spiro-C6: racemate 56

— racemate spiro-C6: racemate

TABLE 9 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 57

— — — 58

R-isomer racemate — 59

racemate racemate — 60

racemate racemate — 61

— racemate — 62

— racemate — 63

S-isomer — —

TABLE 10 Chirality Chirality of at carbon at Ex. benzylic spiro Otherchiral No. Structural formula carbon junction carbon 64

S-isomer racemate — 65

racemate racemate — 66

racemate racemate — 67

— racemate thiazolidine- dione-C5: racemate 68

S-isomer racemate thiazolidine- dione-C5: racemate 69

racemate racemate — 70

S-isomer racemate spiro-C1-C2: cis-isomer

TABLE 11 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 71

racemate racemate — 72

S-isomer racemate — 73

S-isomer — — 74

S-isomer racemate — 75

racemate racemate — 76

S-isomer racemate — 77

R-isomer racemate —

TABLE 12 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 78

S-isomer racemate — 79

racemate racemate — 80

racemate racemate — 81

racemate racemate — 82

racemate racemate — 83

racemate racemate — 84

racemate racemate —

TABLE 13 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 85

racemate racemate — 86

racemate racemate — 87

racemate racemate — 88

— chiral: A — 89

— chiral: B — 90

S-isomer — — 91

S-isomer — —

TABLE 14 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 92

S-isomer — — 93

R-isomer — — 94

R-isomer — — 95

(−)-isomer — — 96

S-isomer — spiro-C5: S-isomer 97

S-isomer — spiro-C5: S-isomer 98

S-isomer — spiro-C2: S-isomer spiro-C5: S-isomer

TABLE 15 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 99

S-isomer — spiro-C2: S-isomer spiro-C5: S-isomer 100

S-isomer — spiro-C2: R-isomer spiro-C5: S-isomer 101

S-isomer — spiro-C2: R-isomer spiro-C5: S-isomer 102

S-isomer — spiro-C5: R-isomer 103

S-isomer — spiro-C5: R-isomer 104

S-isomer — spiro-C2: R-isomer spiro-C5: R-isomer 105

S-isomer — spiro-C2: R-isomer spiro-C5: R-isomer

TABLE 16 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 106

S-isomer — spiro-C2: S-isomer spiro-C5: R-isomer 107

S-isomer — spiro-C2: S-isomer spiro-C5: R-isomer 108

— — — 109

— — — 110

— — — 111

— — — 112

— — —

TABLE 17 Chirality of Chirality carbon at Other Ex. at benzylic spirochiral No. Structural formula carbon junction carbon 113

— racemate — 114

— — spiro structure (axial chirality): racemate 115

— racemate — 116

S-isomer racemate — 117

— — — 118

S-isomer racemate — 119

S-isomer — — 120

(−)-isomer — —

TABLE 18 Ex. No. Compound name 1(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]- hex-4-ynoic acid 2(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]- hex-4-ynoic acidsodium salt 3 (S)-3-[4-(spiro[5.6]dodec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid 4 (S)-3-[4-(spiro[5.6]dodec-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 5(S)-3-[4-(spiro[4.5]dec-7-en-7-ylmethoxy)-phenyl]-hex- 4-ynoic acid 6(S)-3-[4-(spiro[4.5]dec-7-en-7-ylmethoxy)-phenyl]-hex- 4-ynoic acidsodium salt 7 (S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid 8 (S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 9(S)-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]- hex-4-ynoic acid 10(S)-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]- hex-4-ynoic acidsodium salt 11 (S)-3-[4-(spiro[4.4]non-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid 12 (S)-3-[4-(spiro[4.4]non-2-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 13(S)-3-[4-(spiro[4.5]dec-2-en-2-ylmethoxy)-phenyl]-hex- 4-ynoic acid 14(S)-3-[4-(spiro[4.5]dec-2-en-2-ylmethoxy)-phenyl]-hex- 4-ynoic acidsodium salt

TABLE 19 Ex. No. Compound name 15(S)-3-[4-(spiro[4.5]dec-1-en-2-ylmethoxy)-phenyl]-hex- 4-ynoic acid 16(S)-3-[4-(spiro[4.5]dec-1-en-2-ylmethoxy)-phenyl]-hex- 4-ynoic acidsodium salt 17 (S)-3-[4-(spiro[4.4]non-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid 18 (S)-3-[4-(spiro[4.4]non-1-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 19(3S)-3-[4-(11,11-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid 20(3S)-3-[4-(11,11-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 213-[4-(spiro[4.6]undec-2-ylmethoxy)-phenyl]-propionic acid 22(S)-3-[4-(spiro[4.5]dec-8-ylmethoxy)-phenyl]-hex-4- ynoic acid 23(S)-3-[4-(spiro[4.5]dec-8-ylmethoxy)-phenyl]-hex-4- ynoic acid sodiumsalt 24 (S)-3-[4-(spiro[5.5]undec-3-ylmethoxy)-phenyl]-hex-4- ynoic acid25 (S)-3-[4-(spiro[4.5]dec-7-en-8-ylmethoxy)-phenyl]-hex- 4-ynoic acid26 (3S)-3-[4-(spiro[4.5]dec-2-ylmethoxy)-phenyl]-hex-4- ynoic acid 27(3S)-3-[4-(spiro[4.5]dec-2-ylmethoxy)-phenyl]-hex-4- ynoic acid sodiumsalt 28 (3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4- ynoicacid

TABLE 20 Ex. No. Compound name 29(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4- ynoic acid sodiumsalt 30 (3S)-3-[4-(spiro[4.4]non-2-ylmethoxy)-phenyl]-hex-4- ynoic acid31 (3S)-3-[4-(spiro[4.4]non-2-ylmethoxy)-phenyl]-hex-4- ynoic acidsodium salt 32 (3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid (chiral: A) 33(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4- ynoic acid sodiumsalt (chiral: A) 34(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4- ynoic acid(chiral: B) 35 (3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt (chiral: B) 36(3S)-3-[4-(spiro[4.5]dec-7-ylmethoxy)-phenyl]-hex-4- ynoic acid (chiral:A) 37 (3S)-3-[4-(spiro[4.5]dec-7-ylmethoxy)-phenyl]-hex-4- ynoic acidsodium salt (chiral: A) 38(3S)-3-[4-(spiro[4.5]dec-7-ylmethoxy)-phenyl]-hex-4- ynoic acid (chiral:B) 39 (3S)-3-[4-(spiro[4.5]dec-7-ylmethoxy)-phenyl]-hex-4- ynoic acidsodium salt (chiral: B) 403-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid 413-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]- propionic acid42 (−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid

TABLE 21 Ex. No. Compound name 43(−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)- phenyl]-propionicacid sodium salt 44(+)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)- phenyl]-propionicacid 45 3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid sodium salt 463-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid 473-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-ynoic acid 483-[4-(8,8-dimethyl-spiro[5.5]undec-2-ylmethoxy)-phenyl]- propionic acid49 3-[4-(spiro[5.6]dodec-2-ylmethoxy)-phenyl]-propionic acid 503-[4-(7,11-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)- phenyl]-propionicacid 51 3-[4-(7,11-dimethyl-spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid 52 3-[4-(spiro[4.5]dec-2-ylmethoxy)-phenyl]-propionicacid 53 3-[4-(9,9-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)-phenyl]-propionic acid 543-[4-(9,9-dimethyl-spiro[5.5]undec-2-ylmethoxy)-phenyl]- propionic acid55 3-[4-(11,11-dimethyl-spiro[5.5]undec-7-en-2-ylmethoxy)-phenyl]-propionic acid 563-[4-(7,7-dimethyl-spiro[5.5]undec-2-ylmethoxy)-phenyl]- propionic acid

TABLE 22 Ex. No. Compound name 573-[4-(spiro[5.5]undec-3-ylmethoxy)-phenyl]-propionic acid 58(3R)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4- ynoic acid 59N,N-dimethyl-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]- succinamic acid60 3-phenyl-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]- propionic acid61 3-[4-(spiro[5.5]undec-2-yloxy)-phenyl]-propionic acid 623-[4-(2-spiro[5.5]undec-2-yl-ethoxy)-phenyl]-propionic acid 63(3S)-3-[4-(spiro[5.5]undec-3-yloxy)-phenyl]-hex-4- ynoic acid 64(3S)-3-[4-(spiro[5.5]undec-2-yloxy)-phenyl]-hex-4- ynoic acid 65N-methyl-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]- succinamic acid 663-oxazol-2-yl-3-[4-(spiro[5.5]undec-2-ylmethoxy)- phenyl]-propionic acid67 5-[4-(spiro[5.5]undec-2-ylmethoxy)-benzyl]-thiazolidine- 2,4-dione 685-{(1S)-1-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-but-2-ynyl}-thiazolidine-2,4-dione 694-hydroxy-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]- butyric acid 70(3S)-3-[4-(1-hydroxy-spiro[5.5]undec-2-ylmethoxy)- phenyl]-hex-4-ynoicacid

TABLE 23 Ex. No. Compound name 714-methoxy-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]- butyric acid 72(3S)-3-[4-(spiro[5.5]undec-1-ylmethoxy)-phenyl]-hex-4- ynoic acid 73(3S)-3-[4-(spiro[5.5]undec-2-en-3-ylmethoxy)-phenyl]- hex-4-ynoic acid74 (3S)-3-[4-(spiro[5.5]undec-2-yloxy)-phenyl]-hex-4-ynoic acid sodiumsalt 75 3-ethoxy-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]- propionicacid 76 (3S)-3-[4-(spiro[5.5]undec-1-ylmethoxy)-phenyl]-hex-4- ynoicacid sodium salt 77 (Z)-(3R)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hex-4-enoic acid 78(3S)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hexanoic acid 793-ethoxy-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]- propionic acidsodium salt 80 3-methoxy-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid 813-isopropoxy-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]- propionic acid82 3-[4-(spiro[5.5]undec-2-yloxymethyl)-phenyl]-hex-4- ynoic acid 833-propoxy-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]- propionic acid 843-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-hept-4-ynoic acid

TABLE 24 Ex. No. Compound name 853-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-pent-4-ynoic acid 863-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-pent-4-enoic acid 873-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-pentanoic acid 883-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid (chiral: A) 893-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid (chiral: B) 90(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex- 4-ynoic acid0.5 calcium salt 91(S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex- 4-ynoic acid 0.5calcium salt 92 (S)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid L-lysine salt 93(R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex- 4-ynoic acid 94(R)-3-[4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex- 4-ynoic acidL-lysine salt 95 (−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid 0.5 calcium salt 96(3S)-3-[4-((5S)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid 97(3S)-3-[4-((5S)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 98(3S)-3-[4-((2S,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid

TABLE 25 Ex. No. Compound name 99(3S)-3-[4-((2S,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 100(3S)-3-[4-((2R,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid 101(3S)-3-[4-((2R,5S)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 102(3S)-3-[4-((5R)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid 103(3S)-3-[4-((5R)-2-oxo-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 104(3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid 105(3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 106(3S)-3-[4-((2S,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid 107(3S)-3-[4-((2S,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt 1083-[2-chloro-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]- propionic acid109 3-[2-methyl-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]- propionicacid 110 3-[3-hydroxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-propionic acid 1113-[3-methoxy-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]- propionic acid112 3-[3-fluoro-4-(spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]- propionicacid

TABLE 26 Ex. No. Compound name 1133-[6-(spiro[4.5]dec-7-ylmethoxy)-pyridin-3-yl]-propionic acidhydrochloride 114 3-[4-(9-methoxy-spiro[5.5]undec-3-ylmethoxy)-phenyl]-propionic acid 1153-[4-(9,9-dimethyl-spiro[4.5]dec-7-ylmethoxy)-phenyl]- propionic acid116 (3S)-3-[4-(spiro[2.6]non-5-ylmethoxy)-phenyl]-hex-4- ynoic acid 1173-[4-(spiro[3.4]oct-5-en-6-ylmethoxy)-phenyl]-propionic acid 118(3S)-3-[4-(spiro[3.4]oct-6-ylmethoxy)-phenyl]-hex-4- ynoic acid 119(S)-3-[4-(spiro[5.5]undec-2-en-2-ylmethoxy)-phenyl]-hex- 4-ynoic acidL-lysine salt 120 (−)-3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionic acid L-lysine salt

TABLE 27 Ex. No. NMR data of compound 1 ¹H-NMR (CDCl₃) δ: 1.42-1.28(12H, m), 1.84 (3H, d, J = 2.6 Hz), 1.90 (2H, s), 2.05 (2H, s), 2.70(1H, dd, J = 15.8, 6.8 Hz), 2.80 (1H, dd, J = 15.8, 8.5 Hz), 4.06-4.04(1H, m), 5.73 (1H, s), 4.34 (2H, s), 6.86 (2H, d, J = 8.7 Hz), 7.27 (2H,d, J = 8.7 Hz). 2 ¹H-NMR (DMSO-d₆) δ: 1.29-1.18 (4H, m), 1.32-1.43 (8H,m), 1.74 (3H, d, J = 2.6 Hz), 1.84 (2H, s), 1.95-2.02 (2H, m), 2.09 (1H,dd, J = 14.6, 7.42 Hz), 2.2 (1H, dd, J = 14.6, 6.7 Hz), 3.92-4.00 (1H,m), 4.32 (2H, s), 5.68-5.73 (1H, m), 6.79 (2H, d, J = 8.6 Hz), 7.20 (2H,d, J = 8.6 Hz). 3 ¹H-NMR (CDCl₃) δ: 1.36-1.30 (2H, m), 1.40-1.55 (12H,m), 1.81-1.86 (5H, m), 2.00-2.09 (2H, m), 2.71 (1H, dd, J = 15.8, 6.7Hz), 2.80 (1H, dd, J = 15.8, 8.6 Hz), 4.02-4.09 (1H, m), 4.35 (2H, s),5.76-5.80 (1H, m), 6.87 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz). 4¹H-NMR (DMSO-d₆) δ: 1.50-1.23 (14H, m), 1.47 (2H, s), 1.74 (3H, d, J =2.6 Hz), 1.95-2.02 (2H, m), 2.11 (1H, dd, J = 14.6, 7.2 Hz), 2.26 (1H,dd, J = 14.6, 6.5 Hz), 3.93-4.00 (1H, m), 4.32 (2H, s), 5.71-5.76 (1H,m), 6.79 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz). 5 ¹H-NMR(DMSO-d₆) δ: 1.31-1.36 (4H, m), 1.41 (2H, dd, J = 6.4, 6.4 Hz),1.56-1.61 (4H, m), 1.78 (3H, d, J = 2.3 Hz), 1.89 (2H, br s), 2.03-2.07(2H, m), 2.55-2.61 (2H, m), 3.90-3.96 (1H, m), 4.35 (2H, s), 5.74 (1H,s), 6.84-6.88 (2H, m), 7.22-7.26 (2H, m), 12.23 (1H, s). 6 ¹H-NMR(DMSO-d₆) δ: 1.37-1.31 (4H, m), 1.41 (2H, t, J = 6.3 Hz), 1.55-1.62 (4H,m), 1.76 (3H, d, J = 2.4 Hz), 1.87-1.90 (2H, m), 2.01-2.08 (2H, m), 2.11(1H, dd, J = 14.5, 7.2 Hz), 2.27 (1H, dd, J = 14.5, 7.2 Hz), 3.94-4.01(1H, m), 4.33 (2H, s), 5.71-5.75 (1H, m), 6.79 (2H, d, J = 8.5 Hz), 7.21(2H, d, J = 8.5 Hz). 7 ¹H-NMR (DMSO-d₆) δ: 1.39-1.44 (6H, m), 1.57-1.66(6H, m), 1.78 (3H, d, J = 2.3 Hz), 1.98 (2H, dd, J = 5.7, 5.7 Hz),2.57-2.60 (2H, m), 3.91-3.96 (1H, m), 4.33 (2H, s), 5.59 (1H, s), 6.87(2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 12.23 (1H, br s). 8¹H-NMR (DMSO-d₆) δ: 1.40-1.45 (6H, m), 1.57-1.65 (6H, m), 1.75 (3H, d, J= 2.6 Hz), 1.98 (2H, dd, J = 5.6, 5.6 Hz), 2.13 (1H, dd, J = 14.7, 7.3Hz), 2.28 (1H, dd, J = 14.7, 7.3 Hz), 3.94-4.00 (1H, m), 4.31 (2H, s),5.59 (1H, s), 6.81 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.8 Hz). 9¹H-NMR (CDCl₃) δ: 1.66-1.34 (14H, m), 1.84 (3H, d, J = 2.3 Hz), 2.03(2H, t, J = 5.1 Hz), 2.70 (1H, dd, J = 15.5, 6.8 Hz), 2.80 (1H, dd, J =15.5, 8.5 Hz), 4.06-4.03 (1H, m), 4.34 (2H, s), 5.66 (1H, s), 6.87 (2H,d, J = 8.7 Hz), 7.27 (2H, d, J = 8.7 Hz). 10 ¹H-NMR (DMSO-d₆) δ:1.27-1.48 (12H, m), 1.54-1.60 (2H, m), 1.74 (3H, d, J = 2.3 Hz),2.00-1.95 (2H, m), 2.10 (1H, dd, J = 14.6, 6.7 Hz), 2.25 (1H, dd, J =14.6, 6.7 Hz), 3.93-4.00 (1H, m), 4.31 (2H, s), 5.66 (1H, s), 6.80 (2H,d, J = 8.1 Hz), 7.20 (2H, d, J = 8.1 Hz).

TABLE 28 Ex. No. NMR data of compound 11 ¹H-NMR (DMSO-d₆) δ: 1.45-1.55(4H, m), 1.63-1.57 (4H, m), 1.77 (3H, d, J = 2.6 Hz), 2.23-2.26 (4H, m),2.55-2.61 (2H, m), 3.90-3.96 (1H, m), 4.52 (2H, s), 5.61-5.65 (1H, m),6.87 (2H, d, J = 9.0 Hz), 7.24 (2H, d, J = 9.0 Hz), 12.23 (1H, br s). 12¹H-NMR (DMSO-d₆) δ: 1.63-1.48 (8H, m), 1.75 (3H, d, J = 2.0 Hz), 2.12(1H, dd, J = 14.6, 7.4 Hz), 2.23-2.30 (5H, m), 3.94-4.01 (1H, m), 4.50(2H, s), 5.61-5.65 (1H, m), 6.81 (2H, d, J = 8.7 Hz), 7.21 (2H, d, J =8.7 Hz). 13 ¹H-NMR (CDCl₃) δ: 1.49-1.35 (10H, m), 1.83 (3H, d, J = 2.4Hz), 2.18-2.23 (4H, m), 2.70 (1H, dd, J = 15.7, 8.5 Hz), 2.79 (1H, dd, J= 15.7, 8.5 Hz), 4.01-4.08 (1H, m), 4.5 (2H, s), 5.58-5.62 (1H, m), 6.86(2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz). 14 ¹H-NMR (DMSO-d₆) δ:1.45-1.32 (10H, m), 1.75 (3H, d, J = 2.4 Hz), 2.08-2.17 (5H, m), 2.26(1H, dd, J = 14.5, 6.8 Hz), 3.95-3.99 (1H, m), 4.49 (2H, s), 5.56-5.60(1H, m), 6.80 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz). 15 ¹H-NMR(CDCl₃) δ: 1.54-1.27 (10H, m), 1.76 (2H, t, J = 9.6 Hz), 1.85 (3H, d, J= 3.0 Hz), 2.39 (2H, t, J = 6.8 Hz), 2.71 (1H, dd, J = 15.7, 6.6 Hz),2.80 (1H, dd, J = 15.7, 8.5 Hz), 4.52 (2H, s), 4.08-4.03 (1H, m), 5.68(1H, s), 6.88 (2H, d, J = 9.4 Hz), 7.28 (2H, d, J = 9.4 Hz). 16 ¹H-NMR(DMSO-d₆) δ: 1.47-1.30 (10H, m), 1.68 (2H, t, J = 7.2 Hz), 1.74 (3H, d,J = 2.3 Hz), 2.10 (1H, dd, J = 14.6, 7.4 Hz), 2.26 (1H, dd, J = 14.6,6.8 Hz), 2.33 (2H, t, J = 6.8 Hz), 3.99-3.94 (1H, m), 4.49 (2H, s), 5.66(1H, s), 6.81 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz). 17 ¹H-NMR(CDCl₃) δ: 1.68-1.48 (7H, m), 1.86-1.82 (6H, m), 2.40 (2H, t, J = 7.2Hz), 2.71 (1H, dd, J = 15.7, 6.6 Hz), 4.08-4.04 (1H, m), 4.53 (2H, s),5.60 (1H, br s), 6.88 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz). 18¹H-NMR (DMSO-d₆) δ: 1.58-1.50 (8H, m), 1.76-1.73 (5H, m), 2.12 (1H, dd,J = 14.7, 7.5 Hz), 2.28 (1H, dd, J = 14.7, 6.7 Hz), 2.34 (2H, t, J = 7.7Hz), 4.00-3.94 (1H, m), 4.50 (2H, s), 5.59 (1H, s), 6.82 (2H, d, J = 8.7Hz), 7.22 (2H, d, J = 8.7 Hz). 19 ¹H-NMR (CDCl₃) δ: 0.98-0.84 (7H, m),1.14 (1H, t, J = 12.5 Hz), 1.26-1.72 (7H, m), 1.83 (3H, d, J = 2.4 Hz),1.88-2.13 (4H, m), 2.70 (1H, dd, J = 15.7, 6.8 Hz), 2.80 (1H, dd, J =15.7, 8.4 Hz), 3.67-3.74 (2H, m), 4.01-4.08 (1H, m), 5.61 (1H, dt, J =10.6, 3.5 Hz), 5.88 (1H, dt, J = 10.6, 2.0 Hz), 6.84 (2H, d, J = 8.4Hz), 7.27 (2H, d, J = 8.4 Hz). 20 ¹H-NMR (DMSO-d₆) δ: 0.95-0.81 (7H, m),1.13 (1H, t, J = 12.4 Hz), 1.29-1.47 (4H, m), 1.51-1.62 (3H, m), 1.74(3H, d, J = 2.4 Hz), 1.79-1.87 (1H, m), 1.92-2.01 (3H, m), 2.08 (1H, dd,J = 14.7, 7.5 Hz), 2.24 (1H, dd, J = 14.7, 6.7 Hz), 3.70 (2H, d, J = 6.2Hz), 3.92-3.99 (1H, m), 5.59 (1H, dt, J = 10.4, 3.5 Hz), 5.88 (1H, dt, J= 10.4, 2.0 Hz), 6.77 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz).

TABLE 29 Ex. No. NMR data of compound 21 ¹H-NMR (CDCl₃) δ: 1.10 (1H, dd,J = 12.8, 9.3 Hz), 1.48 (15H, m), 1.91-1.77 (2H, m), 2.47-2.39 (1H, m),2.66 (2H, t, J = 7.8 Hz), 2.91 (2H, t, J = 7.8 Hz), 3.82 (2H, d, J = 7.0Hz), 6.83 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz). 22 ¹H-NMR(CDCl₃) δ: 1.44-1.11 (8H, m), 1.65-1.50 (7H, m), 1.77-1.73 (2H, m), 1.84(3H, d, J = 2.6 Hz), 2.71 (1H, dd, J = 15.5, 6.7 Hz), 2.81 (1H, dd, J =15.5, 8.5 Hz), 3.76 (2H, d, J = 6.3 Hz), 4.07-4.04 (1H, m), 6.85 (2H, d,J = 8.0 Hz), 7.28 (2H, d, J = 8.6 Hz). 23 ¹H-NMR (DMSO-d₆) δ: 1.78-1.04(17H, m), 1.74 (3H, d, J = 2.3 Hz), 2.12 (1H, dd, J = 14.5, 7.42 Hz),2.3 (1H, dd, J = 14.5, 6.8 Hz), 3.73 (2H, d, J = 6.0 Hz), 3.93-3.99 (1H,m), 6.78 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz). 24 ¹H-NMR(CDCl₃) δ: 1.28-1.02 (7H, m), 1.40-1.37 (8H, m), 1.68-1.65 (2H, m), 1.80(3H, d, J = 2.2 Hz), 2.77-2.67 (2H, m), 3.73 (2H, d, J = 6.4 Hz),4.04-4.01 (1H, m), 6.82 (2H, d, J = 8.7 Hz), 7.26 (2H, d, J = 8.7 Hz).25 ¹H-NMR (CDCl₃) δ: 1.41-1.38 (4H, m), 1.65-1.51 (6H, m), 1.83 (3H, d,J = 2.3 Hz), 1.94 (2H, s), 2.11 (2H, s), 2.70 (1H, dd, J = 6.8, 14.6Hz), 2.80 (1H, dd, J = 14.6, 7.7 Hz), 4.07-4.01 (1H, m), 4.36 (2H, s),5.73 (1H, s), 6.86 (2H, d, J = 8.7 Hz), 7.27 (2H, d, J = 8.7 Hz). 26¹H-NMR (CDCl₃) δ: 1.11 (1H, dd, J = 12.4, 9.6 Hz), 1.48-1.29 (13H, m),1.85-1.79 (5H, m), 2.44-2.42 (1H, m), 2.84-2.69 (2H, m), 2.84-2.69 (2H,m), 3.82 (2H, d, J = 6.5 Hz), 4.06-4.04 (1H, br m), 6.85 (2H, d, J = 8.1Hz), 7.28 (2H, d, J = 8.1 Hz). 27 ¹H-NMR (DMSO-d₆) δ: 1.07 (1H, dd, J =12.9, 10.4 Hz), 1.47-1.30 (14H, m), 1.78-1.73 (5H, m), 2.11 (1H, dd, J =14.6, 7.4 Hz), 2.26 (1H, dd, J = 14.6, 6.7 Hz), 2.26 (1H, dd, J = 14.6,6.7 Hz), 2.26 (1H, dd, J = 14.6, 6.7 Hz), 2.36 (1H, td, J = 15.5, 7.9Hz), 3.79 (2H, d, J = 7.3 Hz), 4.00-3.94 (1H, m), 6.78 (2H, d, J = 8.8Hz), 7.2 (2H, d, J = 8.8 Hz). 28 ¹H-NMR (CDCl₃) δ: 0.76 (1H, t, J = 12.6Hz), 0.97-0.89 (2H, m), 1.26-1.21 (3H, m), 1.53-1.41 (8H, m), 1.72 (3H,t, J = 16.9 Hz), 1.83 (3H, d, J = 2.3 Hz), 1.92-1.88 (2H, m), 2.70 (1H,dd, J = 15.8, 6.8 Hz), 2.80 (1H, dd, J = 15.6, 8.5 Hz), 3.71-3.67 (2H,m), 4.06-4.03 (1H, m), 6.84 (2H, d, J = 8.7 Hz), 7.27 (2H, d, J = 8.7Hz). 29 ¹H-NMR (DMSO-d₆) δ: 0.75 (1H, t, J = 12.9 Hz), 0.96-0.83 (2H,m), 1.53-1.16 (12H, m), 1.61-1.75 (5H, m), 1.76-1.91 (2H, m), 2.07 (1H,dd, J = 14.6, 7.4 Hz), 2.23 (1H, dd, J = 14.6, 6.7 Hz), 3.64-3.72 (2H,m), 3.92-3.98 (1H, m), 6.77 (2H, d, J = 8.6 Hz), 7.19 (2H, d, J = 8.6Hz). 30 ¹H-NMR (CDCl₃) δ: 1.28 (1H, dd, J = 12.8, 8.7 Hz), 1.63-1.40(9H, br m), 1.86-1.79 (5H, m), 2.47-2.44 (1H, m), 2.47-2.44 (1H, m),2.47-2.44 (1H, m), 2.47-2.44 (1H, m), 2.70 (1H, dd, J = 15.6, 6.8 Hz),2.80 (1H, dd, J = 15.6, 8.5 Hz), 3.82 (2H, d, J = 6.4 Hz), 4.06-4.03(1H, br m), 6.84 (2H, d, J = 8.7 Hz), 7.27 (2H, d, J = 8.7 Hz).

TABLE 30 Ex. No. NMR data of compound 31 ¹H-NMR (DMSO-d₆) δ: 1.25 (1H,dd, J = 12.6, 8.5 Hz), 1.62-1.37 (11H, m), 1.71-1.69 (1H, m), 1.74 (3H,d, J = 2.4 Hz), 1.86-1.77 (1H, m), 2.12 (1H, dd, J = 14.5, 7.5 Hz), 2.28(1H, dd, J = 14.5, 6.9 Hz), 2.44-2.33 (1H, m), 3.80 (2H, dd, J = 7.0,2.0 Hz), 3.98-3.96 (1H, m), 6.79 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J =8.6 Hz). 32 ¹H-NMR (DMSO-d₆) δ: 0.75 (1H, t, J = 12.6 Hz), 0.96-0.84(2H, m), 1.17-1.21 (2H, m), 1.33-1.54 (10H, m), 1.61-1.75 (2H, m), 1.77(3H, d, J = 2.3 Hz), 1.79-1.92 (2H, m), 2.58 (2H, dd, J = 7.5, 1.7 Hz),3.66-3.73 (2H, m), 3.90-3.94 (1H, m), 6.84 (2H, d, J = 8.1 Hz), 7.23(2H, d, J = 8.1 Hz), 12.23 (1H, br s). 33 ¹H-NMR (DMSO-d₆) δ: 0.75 (1H,t, J = 12.68 Hz), 0.97-0.84 (2H, m), 1.16-1.22 (2H, m), 1.32-1.46 (9H,m), 1.47-1.54 (1H, m), 1.61-1.72 (2H, m), 1.75 (3H, d, J = 2.4 Hz),1.80-1.90 (2H, m), 2.10 (1H, dd, J = 14.7, 6.8 Hz), 2.25 (1H, dd, J =14.7, 6.8 Hz), 3.65-3.72 (2H, m), 3.93-4.00 (1H, m), 6.78 (2H, d, J =8.7 Hz), 7.20 (2H, d, J = 8.7 Hz). 34 ¹H-NMR (DMSO-d₆) δ: 0.75 (1H, t, J= 12.5 Hz), 0.96-0.84 (2H, m), 1.15-1.24 (2H, m), 1.33-1.45 (9H, m),1.47-1.54 (1H, m), 1.62-1.91 (7H, m), 2.56-2.59 (2H, m), 3.66-3.73 (2H,m), 3.89-3.95 (1H, m), 6.84 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 8.6Hz), 12.23 (1H, br s). 35 ¹H-NMR (DMSO-d₆) δ: 0.75 (1H, t, J = 12.7 Hz),0.84-0.96 (2H, m), 1.17-1.24 (2H, m), 1.34-1.52 (10H, m), 1.63-1.71 (2H,m), 1.74 (3H, d, J = 2.7 Hz), 1.79-1.91 (2H, m), 2.08 (1H, dd, J = 14.5,7.5 Hz), 2.24 (1H, dd, J = 14.5, 6.8 Hz), 3.65-3.72 (2H, m), 3.93-3.99(1H, m), 6.77 (2H, d, J = 8.7 Hz), 7.20 (2H, d, J = 8.7 Hz). 36 ¹H-NMR(DMSO-d₆) δ: 0.93 (1H, dddd, J = 12.8, 12.8, 12.8, 3.7 Hz), 1.02 (1H,dd, J = 12.8, 12.8 Hz), 1.15 (1H, ddd, J = 12.8, 12.8, 3.7 Hz),1.30-1.48 (6H, m), 1.51-1.63 (6H, m), 1.76-1.82 (2H, m), 1.77 (3H, d, J= 2.4 Hz), 2.57-2.60 (2H, m), 3.68-3.75 (2H, m), 3.90-3.96 (1H, m), 6.84(2H, d, J = 8.4 Hz), 7.24 (2H, d, J = 8.4 Hz), 12.21 (1H, br s). 37¹H-NMR (DMSO-d₆) δ: 0.92 (1H, dddd, J = 12.7, 12.7, 12.7, 3.7 Hz), 1.01(1H, dd, J = 12.7, 6.3 Hz), 1.15 (1H, ddd, J = 12.7, 12.7, 3.7 Hz),1.29-1.47 (6H, m), 1.50-1.62 (6H, m), 1.75 (3H, d, J = 2.3 Hz),1.75-1.82 (2H, m), 2.13 (1H, dd, J = 14.6, 6.9 Hz), 2.28 (1H, dd, J =14.6, 6.9 Hz), 3.66-3.73 (2H, m), 3.94-4.00 (1H, m), 6.78 (2H, d, J =8.5 Hz), 7.21 (2H, d, J = 8.5 Hz). 38 ¹H-NMR (DMSO-d₆) δ: 0.93 (1H,dddd, J = 12.8, 12.8, 12.8, 3.8 Hz), 1.02 (1H, dd, J = 12.8, 12.8 Hz),1.15 (1H, ddd, J = 12.8, 12.8, 3.8 Hz), 1.29-1.47 (6H, m), 1.51-1.63(6H, m), 1.76-1.82 (2H, m), 1.78 (3H, d, J = 2.4 Hz), 2.53-2.63 (2H, m),3.68-3.75 (2H, m), 3.90-3.96 (1H, m), 6.84 (2H, d, J = 8.6 Hz), 7.24(2H, d, J = 8.6 Hz), 12.21 (1H, br s). 39 ¹H-NMR (DMSO-d₆) δ: 0.92 (1H,dddd, J = 12.7, 12.7, 12.7, 3.7 Hz), 1.01 (1H, dd, J = 12.7, 12.7 Hz),1.15 (1H, ddd, J = 12.7, 12.7, 3.7 Hz), 1.29-1.47 (6H, m), 1.50-1.62(6H, m), 1.75 (3H, d, J = 2.6 Hz), 1.76-1.83 (2H, m), 2.24 (1H, dd, J =14.8, 7.3 Hz), 2.37 (1H, dd, J = 14.8, 7.3 Hz), 3.66-3.73 (2H, m),3.93-3.98 (1H, m), 6.79 (2H, d, J = 8.5 Hz), 7.21 (2H, d, J = 8.5 Hz).

TABLE 31 Ex. No. NMR data of compound 40 ¹H-NMR (CDCl₃) δ: 0.76 (1H, t,J = 12.52 Hz), 0.86-0.99 (2H, m), 1.19-1.25 (2H, m), 1.35-1.60 (9H, m),1.66-1.77 (2H, m), 1.83-2.00 (2H, m), 2.06-2.09 (1H, m), 2.88-3.04 (1H,m), 3.41-3.54 (1H, m), 3.64-3.69 (2H, m), 3.78 (3H, s), 4.50-4.63 (1H,m), 6.82 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz). 41 ¹H-NMR(DMSO-d₆) δ: 0.99-1.04 (3H, m), 1.23-1.49 (12H, m), 1.54-1.60 (2H, m),1.95-2.00 (2H, m), 2.45 (1H, dd, J = 5.2, 14.8 Hz), 2.60 (1H, dd, J =8.7, 14.8 Hz), 3.17-3.26 (2H, m), 4.35 (2H, s), 4.57 (1H, dd, J = 8.7,5.2 Hz), 5.66 (1H, s), 6.89 (2H, d, J = 9.0 Hz), 7.19 (2H, d, J = 9.0Hz), 12.11 (1H, br s). 42 ¹H-NMR (CDCl₃) δ: 1.18 (3H, t, J = 7.0 Hz),1.30-1.51 (12H, m), 1.64 (2H, tt, J = 9.2, 3.1 Hz), 2.01-2.16 (2H, m),2.62 (1H, dd, J = 15.7, 4.1 Hz), 2.83 (1H, dd, J = 15.7, 9.7 Hz),3.34-3.47 (2H, m), 4.36 (2H, s), 4.66 (1H, dd, J = 9.5, 4.0 Hz), 5.67(1H, s), 6.91 (2H, dt, J = 9.3, 2.4 Hz), 7.22 (2H, dt, J = 9.2, 2.4 Hz).43 ¹H-NMR (DMSO-d₆) δ: 1.02 (3H, dt, J = 22.9, 7.9 Hz), 1.30-1.60 (13H,m), 1.97-2.07 (3H, m), 2.32 (1H, dd, J = 14.5, 7.0 Hz), 3.13-3.29 (4H,m), 4.34 (2H, s), 4.59 (1H, t, J = 6.5 Hz), 5.67 (1H, s), 6.84 (2H, d, J= 8.5 Hz), 7.16 (2H, d, J = 8.7 Hz). 44 ¹H-NMR (CDCl₃) δ: 1.18 (3H, t, J= 7.0 Hz), 1.30-1.51 (12H, m), 1.64 (2H, tt, J = 9.2, 3.1 Hz), 2.01-2.16(2H, m), 2.62 (1H, dd, J = 15.7, 4.1 Hz), 2.83 (1H, dd, J = 15.7, 9.7Hz), 3.34-3.47 (2H, m), 4.36 (2H, s), 4.66 (1H, dd, J = 9.5, 4.0 Hz),5.67 (1H, s), 6.91 (2H, dt, J = 9.3, 2.4 Hz), 7.22 (2H, dt, J = 9.2, 2.4Hz). 45 ¹H-NMR (DMSO-d₆) δ: 1.01 (3H, t, J = 7.0 Hz), 1.48-1.24 (12H,m), 1.55-1.61 (2H, m), 1.96-2.04 (3H, m), 2.30 (1H, dd, J = 14.4, 7.0Hz), 3.12-3.25 (2H, m), 4.33 (2H, s), 4.58 (1H, t, J = 6.6 Hz), 5.67(1H, s), 6.83 (2H, d, J = 9.3 Hz), 7.15 (2H, d, J = 9.3 Hz). 46 ¹H-NMR(CDCl₃) δ: 0.76 (1H, t, J = 12.6 Hz), 0.97-0.90 (2H, m), 1.30-1.23 (3H,m), 1.57-1.42 (9H, m), 1.76-1.69 (2H, m), 1.96-1.92 (2H, m), 2.65 (2H,t, J = 7.8 Hz), 2.90 (2H, t, J = 7.8 Hz), 3.71-3.67 (2H, m), 6.82 (2H,d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz). 47 ¹H-NMR (CDCl₃) δ: 0.75 (1H,t, J = 12.6 Hz), 0.99-0.83 (2H, m), 1.49-1.24 (11H, br m), 1.87-1.74(8H, m), 2.67 (1H, dd, J = 6.6, 15.6 Hz), 2.77 (1H, dd, J = 8.6, 15.6Hz), 3.70-3.65 (2H, m), 4.06-4.00 (1H, m), 6.82 (2H, d, J = 8.7 Hz),7.26 (2H, d, J = 8.7 Hz). 48 ¹H-NMR (DMSO-d₆) δ: 0.72-1.03 (10H, m),1.15-1.48 (10H, m), 1.64-1.99 (3H, m), 2.45 (2H, t, J = 6.5 Hz), 2.72(2H, t, J = 6.5 Hz), 3.68 (2H, t, J = 13.6 Hz), 6.79 (2H, d, J = 8.6Hz), 7.10 (2H, d, J = 8.6 Hz), 12.10 (1H, s). 49 ¹H-NMR (DMSO-d₆) δ:0.74 (1H, t, J = 12.6 Hz), 0.94-0.87 (2H, m), 1.67 (1H, d, J = 12.4 Hz),1.50-1.36 (15H, m), 2.47 (2H, t, J = 7.5 Hz), 1.81-1.77 (2H, m), 2.74(2H, t, J = 7.5 Hz), 3.32 (2H, s), 3.68 (2H, d, J = 7.0 Hz), 6.80 (2H,d, J = 8.7 Hz), 7.10 (2H, d, J = 8.7 Hz).

TABLE 32 Ex. No. NMR data of compound 50 ¹H-NMR (DMSO-d₆) δ: 0.81 (3H,d, J = 6.8 Hz), 1.01-0.89 (1H, m), 1.18 (1H, t, J = 12.9 Hz), 1.28-2.08(14H, m), 2.12-2.20 (1H, m), 2.47 (2H, t, J = 7.6 Hz), 2.73 (2H, t, J =7.6 Hz), 3.70 (2H, dd, J = 1.9, 6.2 Hz), 5.28-5.33 (1H, m), 6.80 (2H, d,J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz), 12.06 (1H, s). 51 ¹H-NMR(DMSO-d₆) ca. 2:1 diastereomeric mixture δ: 0.76 (2H Me, d, J = 6.8 Hz),0.87 (3H, d, J = 6.6 Hz), 0.98 (1H Me, d, J = 7.3 Hz), 1.15-2.10 (17H,m), 2.47 (3H, t, J = 7.5 Hz), 2.74 (2H, t, J = 7.5 Hz), 3.66-3.76 (2H,m), 6.81 (2H, d, J = 8.6 Hz), 7.10 (2H, d, J = 8.6 Hz), 12.06 (1H, s).52 ¹H-NMR (CDCl₃) δ: 1.10 (1H, dd, J = 13.0, 9.2 Hz), 1.42 (13H, tt, J =17.7, 5.8 Hz), 1.86-1.77 (2H, m), 2.47-2.37 (1H, m), 2.64 (2H, t, J =7.7 Hz), 2.90 (2H, t, J = 7.7 Hz), 3.81 (2H, d, J = 7.2 Hz), 6.82 (2H,d, J = 8.3 Hz), 7.11 (2H, d, J = 8.3 Hz). 53 ¹H-NMR (DMSO-d₆) δ:0.94-1.12 (9H, m), 1.33-1.65 (8H, m), 1.78-2.01 (2H, m), 2.46 (2H, d, J= 7.6 Hz), 2.73 (2H, t, J = 7.6 Hz), 3.66-3.73 (2H, m), 5.11 (0.5H, d, J= 9.9 Hz), 5.29 (0.5H, d, J = 9.9 Hz), 5.34 (0.5H, d, J = 10.4 Hz), 5.82(0.5H, d, J = 10.4 Hz), 6.81 (2H, t, J = 4.3 Hz), 7.10 (2H, d, J = 8.6Hz), 12.07 (1H, s). 54 ¹H-NMR (DMSO-d₆) δ: 0.71-0.94 (9H, m), 1.16-1.26(6H, m), 1.34-1.54 (4H, m), 1.64-1.92 (4H, m), 2.46 (2H, t, J = 7.6 Hz),2.74 (2H, t, J = 7.6 Hz), 3.65-3.73 (2H, m), 6.79-6.82 (2H, m), 7.10(2H, d, J = 8.6 Hz), 12.07 (1H, s). 55 ¹H-NMR (DMSO-d₆) δ: 0.83 (6H, s),0.86-0.95 (1H, m), 1.13 (1H, t, J = 12.5 Hz), 1.46-1.29 (4H, m),1.51-1.62 (3H, m), 1.78-1.86 (1H, m), 1.92-2.03 (3H, m), 2.47 (2H, t, J= 7.5 Hz), 2.74 (2H, t, J = 7.5 Hz), 3.70 (2H, d, J = 7.4 Hz), 5.59 (1H,dt, J = 9.9, 3.1 Hz), 5.9 (1H, dt, J = 10.0, 2.0 Hz), 6.81 (2H, d, J =8.6 Hz), 7.10 (2H, d, J = 8.6 Hz), 12.05 (1H, s). 56 ¹H-NMR (DMSO-d₆) δ:0.77-0.87 (7H, m), 1.02 (1H, t, J = 12.6 Hz), 1.20-1.53 (12H, m),1.61-1.68 (1H, m), 1.74-1.92 (2H, m), 2.47 (2H, t, J = 7.5 Hz), 2.74(2H, t, J = 7.5 Hz), 3.65-3.74 (2H, m), 6.81 (2H, d, J = 8.4 Hz), 7.10(2H, d, J = 8.4 Hz), 12.06 (1H, s). 57 ¹H-NMR (CDCl₃) δ: 1.10-1.06 (2H,m), 1.27-1.21 (4H, m), 1.45-1.40 (8H, m), 1.79-1.63 (5H, m), 2.65 (2H,t, J = 7.8 Hz), 2.91 (2H, t, J = 7.8 Hz), 3.76 (2H, d, J = 6.5 Hz), 6.83(2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz). 58 ¹H-NMR (CDCl₃) δ: 0.73(1H, t, J = 12.8 Hz), 0.96-0.88 (2H, m), 1.51-1.21 (11H, m), 1.69-1.65(6H, m), 1.88-1.84 (2H, m), 2.51 (1H, dd, J = 15.6, 6.8 Hz), 2.62 (1H,dd, J = 15.6, 8.6 Hz), 3.62-3.57 (2H, m), 3.98-3.95 (1H, m), 6.73 (2H,d, J = 8.6 Hz), 7.18 (2H, d, J = 8.6 Hz). 59 ¹H-NMR (DMSO-d₆) δ: 0.75(1H, t, J = 12.7 Hz), 0.86-0.96 (2H, m), 1.16-1.22 (2H, m), 1.33-1.54(10H, m), 1.61-1.92 (4H, m), 2.36 (1H, dd, J = 16.8, 4.6 Hz), 2.79 (3H,s), 2.85-2.93 (4H, m), 3.67-3.72 (2H, m), 4.21 (1H, dd, J = 10.1, 4.6Hz), 6.85 (2H, d, J = 8.6 Hz), 7.16 (2H, d, J = 8.6 Hz), 12.06 (1H, brs).

TABLE 33 Ex. No. NMR data of compound 60 ¹H-NMR (DMSO-d₆) δ: 0.74 (1H,dd, J = 12.6, 12.6 Hz), 0.83-0.95 (2H, m), 1.16-1.24 (2H, m), 1.32-1.52(10H, m), 1.61-1.73 (2H, m), 1.76-1.90 (2H, m), 2.96 (2H, d, J = 8.0Hz), 3.65 (1H, dd, J = 8.7, 6.3 Hz), 3.68 (1H, dd, J = 8.7, 6.3 Hz),4.34 (1H, t, J = 8.0 Hz), 6.80 (2H, d, J = 8.8 Hz), 7.12-7.20 (3H, m),7.23-7.29 (4H, m), 12.06 (1H, br s). 61 ¹H-NMR (CDCl₃) δ: 0.87-0.90 (1H,m), 1.02-1.17 (2H, m), 1.24-1.69 (13H, m), 2.03-2.10 (2H, m), 2.65 (2H,dt, J = 7.4, 3.6 Hz), 2.90 (2H, t, J = 7.7 Hz), 4.32 (1H, tt, J = 10.6,4.2 Hz), 6.81 (2H, dt, J = 9.2, 2.5 Hz), 7.08-7.11 (2H, m). 62 ¹H-NMR(CDCl₃) δ: 0.65-0.94 (3H, m), 1.17-1.52 (12H, m), 1.59-1.78 (6H, m),2.65 (2H, dt, J = 7.2, 3.6 Hz), 2.90 (2H, t, J = 7.7 Hz), 3.96 (2H, t, J= 6.6 Hz), 6.83 (2H, dt, J = 9.3, 2.5 Hz), 7.11 (2H, dt, J = 9.3, 2.5Hz). 63 ¹H-NMR (DMSO-d₆) δ: 1.18-1.60 (14H, m), 1.74-1.78 (5H, m), 2.50(2H, t, J = 7.7 Hz), 2.57 (2H, t, J = 7.7 Hz), 3.92 (1H, td, J = 7.6,2.4 Hz), 4.28 (1H, td, J = 8.3, 4.0 Hz), 6.85 (2H, t, J = 4.3 Hz), 7.23(2H, d, J = 8.6 Hz), 12.22 (1H, s). 64 ¹H-NMR (CDCl₃) δ: 1.79-0.92 (16H,m), 1.82-1.85 (3H, m), 2.02-2.12 (2H, m), 2.68-2.83 (2H, m), 4.01-4.08(1H, m), 4.29-4.38 (1H, m), 6.81-6.86 (2H, m), 7.25-7.29 (2H, m). 65¹H-NMR (CDCl₃) δ: 0.72-0.81 (1H, m), 0.87-0.99 (2H, m), 1.18-1.27 (2H,m), 1.37-1.50 (8H, m), 1.51-1.60 (1H, m), 1.65-1.79 (2H, m), 1.83-2.01(2H, m), 2.67 (1H, dd, J = 16.3, 4.63 Hz), 2.75 (3H, d, J = 4.6 Hz),3.26 (1H, dd, J = 16.3, 9.0 Hz), 3.65-3.77 (2H, m), 3.85 (1H, dd, J =9.0, 4.6 Hz), 5.49-5.69 (1H, m), 6.81-6.89 (2H, m), 7.12-7.21 (2H, m).66 ¹H-NMR (DMSO-d₆) δ: 0.74 (1H, dd, J = 12.6, 12.6 Hz), 0.84-0.95 (2H,m), 1.17-1.24 (2H, m), 1.34-1.52 (10H, m), 1.62-1.73 (2H, m), 1.77-1.92(2H, m), 2.78 (1H, dd, J = 16.5, 6.3 Hz), 3.13 (1H, dd, J = 16.5, 9.2Hz), 3.65-3.73 (2H, m), 4.48 (1H, dd, J = 9.2, 6.3 Hz), 6.84 (2H, d, J =8.6 Hz), 7.11 (1H, s), 7.13 (2H, d, J = 8.6 Hz), 7.95 (1H, s), 12.39(1H, br s). 67 ¹H-NMR (CDCl₃) δ: 0.77 (1H, t, J = 12.6 Hz), 1.00-0.87(2H, m), 1.28-1.20 (3H, m), 1.45 (9H, m), 1.73 (2H, t, J = 15.8 Hz),1.98-1.86 (2H, m), 3.10 (1H, dd, J = 14.1, 9.4 Hz), 3.45 (1H, dd, J =14.1, 4.0 Hz), 3.69 (2H, dd, J = 7.0, 2.0 Hz), 4.50 (1H, dd, J = 9.6,4.0 Hz), 6.84 (2H, d, J = 8.7 Hz), 7.13 (2H, d, J = 8.7 Hz), 7.87 (1H,s). 68 ¹H-NMR (CDCl₃) δ: 0.79-0.75 (1H, m), 0.96-0.90 (2H, m), 1.28-1.20(3H, m), 1.48-1.41 (10H, m), 1.72 (2H, t, J = 15.3 Hz), 1.89 (3H, d, J =2.8 Hz), 1.96-1.95 (1H, m), 3.70-3.67 (2H, m), 4.49 (1H, d, J = 3.4 Hz),4.65-4.64 (1H, m), 6.86 (2H, d, J = 8.7 Hz), 7.31 (2H, d, J = 8.7 Hz).69 ¹H-NMR (DMSO-d₆) δ: 0.76 (1H, dd, J = 12.6, 12.6 Hz), 0.85-0.96 (2H,m), 1.17-1.22 (2H, m), 1.33-1.53 (10H, m), 1.63-1.75 (2H, m), 1.78-1.92(2H, m), 2.37 (1H, dd, J = 15.5, 9.6 Hz), 2.72 (1H, dd, J = 15.5, 5.4Hz), 3.00-3.07 (1H, m), 3.39 (1H, dd, J = 10.0, 7.5 Hz), 3.46 (1H, dd, J= 10.0, 6.0 Hz), 3.67 (1H, dd, J = 9.6, 6.0 Hz), 3.70 (1H, dd, J = 9.6,6.0 Hz), 4.69 (1H, brs), 6.80 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5Hz), 11.88 (1H, br s).

TABLE 34 Ex. No. NMR data of compound 70 ¹H-NMR (CDCl₃) δ: 1.52-1.24(16H, m), 1.83 (3H, d, J = 2.64 Hz), 2.14 (1H, s), 2.69 (1H, dd, J =15.64, 6.59 Hz), 2.79 (1H, dd, J = 15.60, 7.80 Hz), 3.70 (1H, s), 3.87(1H, dd, J = 9.23, 5.46 Hz), 4.04-4.01 (2H, m), 6.86 (2H, d, J = 8.67Hz), 7.28 (2H, d, J = 8.70 Hz). 71 ¹H-NMR (DMSO-d₆) δ: 0.76 (1H, dd, J =12.6, 12.6 Hz), 0.85-0.96 (2H, m), 1.17-1.24 (2H, m), 1.35-1.53 (10H,m), 1.63-1.75 (2H, m), 1.79-1.91 (2H, m), 2.37 (1H, dd, J = 15.7, 8.7Hz), 2.58 (1H, dd, J = 15.7, 6.1 Hz), 3.19 (3H, s), 3.21-3.24 (1H, m),3.36-3.40 (2H, m), 3.67 (1H, dd, J = 9.5, 6.0 Hz), 3.70 (1H, dd, J =9.5, 6.0 Hz), 6.80 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz). 72¹H-NMR (CDCl₃) δ: 1.05-0.99 (1H, m), 1.17-1.10 (1H, m), 1.80-1.21 (16H,m), 1.83 (3H, d, J = 2.4 Hz), 1.91-1.87 (1H, m), 2.71 (1H, dd, J = 15.6,6.7 Hz), 2.80 (1H, dd, J = 15.6, 8.4 Hz), 3.74 (1H, t, J = 8.8 Hz),4.07-4.02 (1H, m), 4.15 (1H, dd, J = 9.3, 4.0 Hz), 6.85 (2H, d, J = 8.8Hz), 7.28 (6H, d, J = 8.8 Hz). 73 ¹H-NMR (CDCl₃) δ: 1.30-1.24 (4H, m),1.50-1.40 (8H, m), 1.83 (3H, d, J = 2.2 Hz), 1.90 (2H, s), 2.05 (2H, s),2.70 (1H, dd, J = 15.7, 6.6 Hz), 2.79 (1H, dd, J = 15.7, 8.6 Hz),4.06-4.02 (1H, m), 4.34 (2H, s), 5.70 (1H, s), 6.86 (2H, d, J = 8.6 Hz),7.27 (2H, d, J = 8.6 Hz). 74 ¹H-NMR (DMSO-d₆) δ: 1.00-1.58 (16H, m),1.74 (3H, d, J = 2.4 Hz), 2.03-1.90 (2H, m), 2.08 (1H, dd, J = 14.3, 6.6Hz), 2.23 (1H, dd, J = 14.3, 6.6 Hz), 3.92-3.99 (1H, m), 4.32-4.40 (1H,m), 6.76 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz). 75 ¹H-NMR(CDCl₃) δ: 0.88-0.99 (2H, m), 1.17-1.28 (6H, m), 1.42-2.01 (14H, m),2.62 (1H, dd, J = 15.66, 3.97 Hz), 2.83 (1H, dd, J = 15.8, 9.6 Hz),3.34-3.47 (2H, m), 3.71 (2H, ddd, J = 13.5, 7.3, 4.7 Hz), 4.66 (1H, dd,J = 9.7, 4.0 Hz), 6.88 (2H, dt, J = 10.9, 3.5 Hz), 7.22 (2H, dt, J =9.2, 2.4 Hz). 76 ¹H-NMR (DMSO-d₆) δ: 1.02-0.99 (1H, m), 1.75-1.13 (17H,m), 1.90-1.85 (1H, m), 2.12 (1H, dd, J = 14.7, 7.4 Hz), 2.28 (1H, dd, J= 14.7, 6.8 Hz), 3.72 (1H, t, J = 8.6 Hz) 3.98-3.93 (1H, m), 4.11 (1H,dd, J = 9.6, 4.0 Hz), 6.81 (2H, d, J = 8.6 Hz), 7.21 (2H, d, J = 8.6Hz). 77 ¹H-NMR (CDCl₃) δ: 0.75 (1H, t, J = 12.6 Hz), 0.97-0.90 (2H, m),1.22-1.20 (3H, m), 1.77-1.41 (13H, m), 1.90-1.85 (3H, m), 2.63 (1H, dd,J = 15.1, 8.7 Hz), 2.74 (1H, dd, J = 15.1, 6.8 Hz), 3.68 (2H, dd, J =6.0, 3.0 Hz), 4.16-4.10 (1H, m), 5.55-5.51 (2H, m), 6.82 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.6 Hz). 78 ¹H-NMR (CDCl₃) δ: 1.00-0.72 (6H, m),1.22-1.14 (4H, m), 1.75-1.51 (13H, m), 1.97-1.86 (2H, m), 2.66-2.51 (2H,m), 3.08-2.98 (1H, m), 3.62 (2H, m), 3.70-3.66 (2H, m), 6.81 (2H, d, J =8.2 Hz), 7.07 (2H, d, J = 8.2 Hz). 79 ¹H-NMR (DMSO-d₆) δ: 0.73-0.96 (3H,m), 1.01 (3H, t, J = 7.0 Hz), 1.18-1.88 (16H, m), 2.05 (1H, dd, J =14.5, 6.5 Hz), 2.33 (1H, dd, J = 14.5, 7.0 Hz), 3.13-3.26 (2H, m),3.66-3.74 (2H, m), 4.59 (1H, t, J = 6.6 Hz), 6.81 (2H, d, J = 8.6 Hz),7.16 (2H, d, J = 8.6 Hz).

TABLE 35 Ex. No. NMR data of compound 80 ¹H-NMR (CDCl₃) δ: 0.75-1.00(3H, m), 1.21-1.26 (2H, m), 1.43-2.01 (14H, m), 2.63 (1H, dd, J = 15.7,4.1 Hz), 2.85 (1H, dd, J = 15.7, 9.5 Hz), 3.24 (3H, s), 3.69-3.77 (2H,m), 4.57 (1H, dd, J = 9.5, 4.2 Hz), 6.90 (2H, ddd, J = 9.0, 4.4, 2.1Hz), 7.24 (2H, dt, J = 9.3, 2.4 Hz). 81 ¹H-NMR (CDCl₃) δ: 0.75-1.00 (3H,m), 1.10 (3H, d, J = 6.3 Hz), 1.19 (3H, d, J = 6.0 Hz), 1.21-1.26 (2H,m), 1.43-1.79 (12H, m), 1.88-2.04 (2H, m), 2.61 (1H, dd, J = 15.7, 3.8Hz), 2.80 (1H, dd, J = 15.7, 9.6 Hz), 3.53-3.62 (1H, m), 3.73 (2H, dq, J= 15.6, 5.0 Hz), 4.79 (1H, dd, J = 9.6, 3.8 Hz), 6.87-6.90 (2H, m),7.22-7.27 (2H, m). 82 ¹H-NMR (DMSO-d₆) δ: 0.77-1.57 (16H, m), 1.78 (3H,d, J = 2.3 Hz), 1.87-1.99 (2H, m), 2.62 (2H, d, J = 7.7 Hz), 3.34-3.53(1H, m), 3.96-4.01 (1H, m), 4.45 (2H, s), 7.25 (2H, d, J = 8.1 Hz), 7.32(2H, d, J = 8.1 Hz), 12.26 (1H, br s). 83 ¹H-NMR (CDCl₃) δ: 0.78 (1H, t,J = 12.6 Hz), 0.90 (3H, dd, J = 12.6, 5.2 Hz), 0.94-1.00 (1H, m), 1.22(2H, dt, J = 17.9, 5.2 Hz), 1.43-1.79 (15H, m), 1.88-2.03 (2H, m), 2.63(1H, dt, J = 11.8, 3.9 Hz), 2.84 (1H, dd, J = 15.7, 9.9 Hz), 3.26-3.37(2H, m), 3.73 (2H, tt, J = 10.2, 4.1 Hz), 4.66 (1H, dd, J = 9.7, 3.7Hz), 6.88-6.91 (2H, m), 7.23 (2H, ddd, J = 9.7, 5.3, 2.9 Hz). 84 ¹H-NMR(CDCl₃) δ: 0.76 (1H, t, J = 12.7 Hz), 0.86- 0.99 (2H, m), 1.13 (3H, t, J= 7.5 Hz), 1.20-1.27 (3H, m), 1.37-2.03 (13H, m), 2.21 (2H, ddd, J =15.0, 7.5, 2.2 Hz), 2.75 (2H, ddd, J = 33.4, 15.5, 7.6 Hz), 3.65-3.73(2H, m), 4.06 (1H, td, J = 6.5, 2.1 Hz), 6.82-6.85 (2H, m), 7.27-7.30(2H, m). 85 ¹H-NMR (CDCl₃) δ: 0.76 (1H, t, J = 12.6 Hz), 0.86-0.99 (2H,m), 1.20-1.24 (2H, m), 1.38-1.49 (8H, m), 1.51-1.59 (1H, m), 1.65-1.79(2H, m), 1.85-2.00 (2H, m), 2.29 (1H, d, J = 2.4 Hz), 2.76 (1H, dd, J =15.9, 6.4 Hz), 2.87 (1H, dd, J = 15.9, 8.4 Hz), 3.65-3.73 (2H, m),4.08-4.13 (1H, m), 6.85 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz).86 ¹H-NMR (DMSO-d₆) δ: 0.75 (1H, dd, J = 12.6, 12.6 Hz), 0.85-0.96 (2H,m), 1.18-1.24 (2H, m), 1.34-1.53 (10H, m), 1.62-1.75 (2H, m), 1.79-1.92(2H, m), 2.54 (1H, dd, J = 15.4, 7.5 Hz), 2.63 (1H, dd, J = 15.4, 7.5Hz), 3.65-3.73 (3H, m), 4.98 (2H, br d, J = 14.0 Hz), 5.89-5.98 (1H, m),6.83 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.6 Hz), 12.06 (1H, br s). 87¹H-NMR (DMSO-d₆) δ: 0.69 (3H, dd, J = 7.4, 7.4 Hz), 0.76 (1H, dd, J =12.6, 12.6 Hz), 0.85-0.97 (2H, m), 1.18-1.24 (2H, m), 1.35-1.53 (11H,m), 1.56-1.75 (3H, m), 1.79-1.92 (2H, m), 2.39 (1H, dd, J = 15.3, 8.0Hz), 2.53 (1H, dd, J = 15.3, 6.5 Hz), 2.77-2.84 (1H, m), 3.65-3.73 (2H,m), 6.81 (2H, d, J = 8.6 Hz), 7.08 (2H, d, J = 8.6 Hz), 11.93 (1H, brs). 88 ¹H-NMR (CDCl₃) δ: 0.77 (1H, t, J = 12.6 Hz), 1.00-0.87 (2H, m),1.21-1.27 (2H, m), 1.39-1.59 (10H, m), 1.67-1.81 (2H, m), 1.88-2.01 (2H,m), 2.66 (2H, t, J = 7.8 Hz), 2.91 (2H, t, J = 7.8 Hz), 3.66-3.74 (2H,m), 6.83 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz). 89 ¹H-NMR(CDCl₃) δ: 0.77 (1H, t, J = 12.6 Hz), 1.01-0.87 (2H, m), 1.20-1.27 (2H,m), 1.39-1.59 (10H, m), 1.66-1.80 (2H, m), 1.86-2.01 (2H, m), 2.66 (2H,t, J = 7.7 Hz), 2.91 (2H, t, J = 7.7 Hz), 3.66-3.74 (2H, m), 6.83 (2H,d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz).

TABLE 36 Ex. No. NMR data of compound 90 ¹H-NMR (DMSO-d₆) δ: 1.19-1.43(12H, m), 1.74 (3H, s), 1.82-1.84 (2H, m), 1.95-2.02 (2H, m), 2.19-2.28(1H, m), 2.34-2.44 (1H, m), 3.97-4.06 (1H, m), 4.31 (2H, s), 5.69 (1H,s), 6.79 (2H, d, J = 7.2 Hz), 7.23 (2H, d, J = 7.2 Hz). 91 ¹H-NMR(DMSO-d₆) δ: 1.38-1.45 (6H, m), 1.55-1.65 (6H, m), 1.74 (3H, d, J = 2.3Hz), 1.96 (2H, t, J = 5.7 Hz), 2.19-2.28 (1H, m), 2.34-2.44 (1H, m),4.05-3.97 (1H, m), 4.29 (2H, s), 5.57 (1H, s), 6.81 (2H, d, J = 8.6 Hz),7.23 (2H, d, J = 8.6 Hz). 92 ¹H-NMR (DMSO-d₆) δ: 1.27-1.39 (8H, m),1.47-1.74 (13H, m), 1.91 (2H, t, J = 5.7 Hz), 2.23 (1H, dd, J = 14.7,7.0 Hz), 2.31 (1H, dd, J = 14.7, 8.0 Hz), 2.73 (2H, t, J = 7.5 Hz), 3.28(1H, t, J = 6.0 Hz), 3.84-3.91 (1H, m), 4.27 (2H, s), 5.53 (1H, s), 6.79(2H, d, J = 8.6 Hz), 7.18 (2H, d, J = 8.6 Hz). 93 ¹H-NMR (DMSO-d₆) δ:1.38-1.44 (6H, m), 1.56-1.65 (6H, m), 1.77 (3H, d, J = 2.6 Hz), 1.97(2H, t, J = 6.3 Hz), 2.58 (2H, dd, J = 8.1, 1.9 Hz), 3.89-3.96 (1H, m),4.32 (2H, s), 5.59 (1H, s), 6.86 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J =8.8 Hz), 12.22 (1H, s). 94 ¹H-NMR (DMSO-d₆) δ: 1.27-1.42 (8H, m),1.44-1.52 (2H, m), 1.53-1.70 (8H, m), 1.73 (3H, d, J = 2.3 Hz), 1.94(2H, t, J = 5.9 Hz), 2.28 (2H, dq, J = 40.2, 7.4 Hz), 2.68 (2H, t, J =7.3 Hz), 3.19 (1H, t, J = 6.6 Hz), 3.88-3.95 (1H, m), 4.29 (2H, s), 5.56(1H, s), 6.80 (2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 8.8 Hz). 95 ¹H-NMR(DMSO-d₆) δ: 1.02 (3H, t, J = 7.1 Hz), 1.27-1.48 (12H, m), 1.54-1.62(2H, m), 1.95-2.01 (2H, m), 2.08-2.17 (1H, m), 2.31-2.44 (1H, m),3.15-3.28 (2H, m), 4.34 (2H, s), 4.61 (1H, t, J = 6.7 Hz), 5.67 (1H, s),6.85 (2H, d, J = 8.6 Hz), 7.18 (2H, d, J = 8.6 Hz). 96 ¹H-NMR (DMSO-d₆)δ: 1.42-1.71 (4H, m), 1.77 (3H, d, J = 2.6 Hz), 1.79-1.85 (2H, m),1.98-2.07 (3H, m), 2.16-2.27 (3H, m), 2.56-2.60 (2H, m), 3.90-3.96 (1H,m), 4.36 (2H, s), 5.69 (1H, s), 6.87 (2H, d, J = 8.8 Hz), 7.25 (2H, d, J= 8.8 Hz),12.13 (1H, br s). 97 ¹H-NMR (DMSO-d₆) δ: 1.42-1.71 (4H, m),1.74 (3H, d, J = 2.3 Hz), 1.79-1.85 (2H, m), 1.98-2.11 (4H, m),2.17-2.27 (4H, m), 3.92-3.99 (1H, m), 4.33 (2H, s), 5.69 (1H, s), 6.81(2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz). 98 ¹H-NMR (DMSO-d₆) δ:1.35-1.42 (2H, m), 1.47-1.63 (6H, m), 1.65-1.71 (1H, m), 1.77 (3H, d, J= 2.3 Hz), 1.80-1.90 (1H, m), 1.92-1.97 (2H, m), 2.55-2.59 (2H, m),3.89-3.95 (1H, m), 4.13-4.19 (1H, m), 4.30 (2H, s), 4.48 (1H, br s),5.57 (1H, s), 6.86 (2H, d, J = 8.8 Hz), 7.23 (3H, d, J = 8.8 Hz), 12.28(1H, br s). 99 ¹H-NMR (DMSO-d₆) δ: 1.34-1.42 (2H, m), 1.47-1.62 (6H, m),1.64-1.71 (1H, m), 1.74 (3H, d, J = 2.6 Hz), 1.80-1.89 (1H, m),1.92-1.97 (2H, m), 2.09 (1H, dd, J = 14.6, 7.0 Hz), 2.25 (1H, dd, J =14.6, 7.0 Hz), 3.96 (1H, td, J = 7.0, 2.6 Hz), 4.12-4.18 (1H, m), 4.29(2H, s), 4.55 (1H, br s), 5.56 (1H, s), 6.79 (2H, d, J = 8.6 Hz), 7.20(2H, d, J = 8.6 Hz).

TABLE 37 Ex. No. NMR data of compound 100 ¹H-NMR (DMSO-d₆) δ: 1.35-1.42(4H, m), 1.47-1.71 (5H, m), 1.77 (3H, d, J = 2.3 Hz), 1.78-1.85 (1H, m),1.92-1.97 (2H, m), 2.56 (2H, dd, J = 7.7, 2.3 Hz), 3.93 (1H, td, J =7.7, 2.3 Hz), 4.13-4.18 (1H, m), 4.32 (2H, s), 5.69 (1H, s), 6.86 (2H,d, J = 8.6 Hz), 7.24 (2H, d, J = 8.6 Hz). 101 ¹H-NMR (DMSO-d₆) δ:1.35-1.42 (4H, m), 1.47-1.71 (5H, m), 1.74 (3H, d, J = 2.3 Hz),1.77-1.85 (1H, m), 1.91-1.96 (2H, m), 2.09 (1H, dd, J = 14.6, 7.4 Hz),2.25 (1H, dd, J = 14.6, 7.4 Hz), 3.96 (1H, td, J = 7.4, 2.3 Hz),4.12-4.18 (1H, m), 4.30 (2H, s), 4.52 (1H, brs), 5.67 (1H, s), 6.80 (2H,d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz). 102 ¹H-NMR (DMSO-d₆) δ:1.44-1.70 (4H, m), 1.77 (3H, d, J = 2.4 Hz), 1.80-1.85 (2H, m),1.99-2.08 (3H, m), 2.16-2.27 (3H, m), 2.57 (2H, dd, J = 8.2, 2.4 Hz),3.94 (1H, td, J = 8.2, 2.4 Hz), 4.36 (2H, s), 5.70 (1H, s), 6.88 (2H, d,J = 8.6 Hz), 7.25 (3H, d, J = 8.6 Hz). 103 ¹H-NMR (DMSO-d₆) δ: 1.42-1.70(4H, m), 1.74 (3H, d, J = 2.3 Hz), 1.78-1.85 (2H, m), 1.98-2.30 (8H, m),3.96 (1H, td, J = 7.0, 2.3 Hz), 4.33 (2H, s), 5.69 (1H, s), 6.81 (2H, d,J = 8.6 Hz), 7.21 (2H, d, J = 8.6 Hz). 104 ¹H-NMR (DMSO-d₆) δ: 1.36-1.44(2H, m), 1.48-1.64 (6H, m), 1.66-1.73 (1H, m), 1.77 (3H, d, J = 2.4 Hz),1.81-1.90 (1H, m), 1.93-1.98 (2H, m), 2.57 (2H, dd, J = 7.6, 2.4 Hz),3.93 (1H, td, J = 7.6, 2.4 Hz), 4.14-4.20 (1H, m), 4.31 (2H, s), 5.58(1H, s), 6.86 (2H, d, J = 8.6 Hz), 7.24 (2H, d, J = 8.6 Hz). 105 ¹H-NMR(DMSO-d₆) δ: 1.35-1.43 (2H, m), 1.48-1.63 (6H, m), 1.68 (1H, dd, J =13.3, 6.7 Hz), 1.74 (3H, d, J = 2.4 Hz), 1.80-1.89 (1H, m), 1.93-1.98(2H, m), 2.09 (1H, dd, J = 14.6, 7.5 Hz), 2.24 (1H, dd, J = 14.6, 7.5Hz), 3.93-4.00 (1H, m), 4.13-4.19 (1H, m), 4.29 (2H, s), 4.53 (1H, brs),5.56 (1H, s), 6.79 (2H, d, J = 8.6 Hz), 7.20 (2H, d, J = 8.6 Hz). 106¹H-NMR (DMSO-d₆) δ: 1.35-1.43 (4H, m), 1.47-1.71 (5H, m), 1.77 (3H, d, J= 2.3 Hz), 1.78-1.85 (1H, m), 1.92-1.97 (2H, m), 2.52-2.57 (2H, m), 3.93(1H, td, J = 7.5, 2.3 Hz), 4.13-4.19 (1H, m), 4.32 (2H, s), 5.69 (1H,s), 6.86 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.8 Hz). 107 ¹H-NMR(DMSO-d₆) δ: 1.35-1.42 (4H, m), 1.47-1.71 (5H, m), 1.74 (3H, d, J = 2.6Hz), 1.77-1.85 (1H, m), 1.92-1.97 (2H, m), 2.09 (1H, dd, J = 14.5, 7.5Hz), 2.24 (1H, dd, J = 14.6, 7.5 Hz), 3.96 (1H, td, J = 7.5, 2.6 Hz),4.12-4.19 (1H, m), 4.30 (2H, s), 4.51 (1H, brs), 5.67 (1H, s), 6.80 (2H,d, J = 8.8 Hz), 7.20 (2H, d, J = 8.8 Hz). 108 ¹H-NMR (DMSO-d₆) δ:1.38-1.43 (6H, m), 1.55-1.65 (6H, m), 1.94-1.96 (2H, m), 2.45-2.52 (2H,m), 2.83 (2H, t, J = 7.7 Hz), 4.34 (2H, d, J = 15.3 Hz), 5.60 (1H, s),6.85 (1H, dd, J = 8.5, 2.7 Hz), 7.00 (1H, d, J = 2.6 Hz), 7.22 (1H, d, J= 8.7 Hz), 12.17 (1H, s). 109 ¹H-NMR (DMSO-d₆) δ: 1.46-1.49 (6H, m),1.62-1.70 (6H, m), 1.96 (2H, t, J = 5.7 Hz), 2.21 (3H, s), 2.42 (2H, t,J = 7.8 Hz), 2.71 (2H, t, J = 7.8 Hz), 4.29 (2H, s), 5.58 (1H, s), 6.66(1H, dd, J = 8.4, 2.8 Hz), 6.72 (1H, d, J = 2.88 Hz), 7.01 (1H, d, J =8.4 Hz), 12.08 (1H, s).

TABLE 38 Ex. No. NMR data of compound 110 ¹H-NMR (CDCl₃) δ: 1.46-1.49(6H, m), 1.62-1.70 (6H, m), 2.02-2.05 (2H, m), 2.65 (2H, dt, J = 7.3,3.5 Hz), 2.88 (2H, t, J = 7.8 Hz), 4.40 (2H, s), 5.59 (1H, s), 5.64 (1H,d, J = 12.5 Hz), 6.66 (1H, dd, J = 8.2, 2.2 Hz), 6.79 (2H, t, J = 4.1Hz). 111 ¹H-NMR (CDCl₃) δ: 1.41-1.51 (6H, m), 1.59-1.70 (6H, m), 2.06(2H, t, J = 7.0 Hz), 2.67 (2H, t, J = 8.0 Hz), 2.91 (2H, t, J = 8.0 Hz),3.85 (3H, s), 4.42 (2H, s), 5.57 (1H, s), 6.67-6.78 (2H, m), 6.80-6.87(1H, m). 112 ¹H-NMR (DMSO-d₆) δ: 1.38-1.42 (6H, m), 1.55-1.63 (6H, m),1.98 (2H, t, J = 5.68 Hz), 2.47-2.50 (2H, m), 2.74 (2H, t, J = 7.54 Hz),4.40 (2H, d, J = 9.3 Hz), 5.58 (1H, s), 6.93 (1H, dd, J = 8.45, 1.2 Hz),7.02 (1H, d, J = 8.8 Hz), 7.05-7.08 (1H, m), 12.11 (1H, s). 113 ¹H-NMR(CDCl₃) δ: 0.97-1.22 (3H, m), 1.35-1.50 (6H, m), 1.54-1.69 (6H, m), 1.88(1H, d, J = 12.8 Hz), 1.95-2.03 (1H, m), 2.75 (2H, t, J = 6.8 Hz), 2.99(2H, t, J = 6.8 Hz), 4.31 (1H, dd, J = 9.5, 6.2 Hz), 4.35 (1H, dd, J =9.5, 6.2 Hz), 7.08 (1H, d, J = 8.8 Hz), 8.05 (1H, dd, J = 8.8, 2.2 Hz),8.33 (1H, d, J = 2.2 Hz). 114 ¹H-NMR (CDCl₃) δ: 0.99-1.30 (6H, m),1.34-1.52 (4H, m), 1.67-1.91 (7H, m), 2.64 (2H, t, J = 7.8 Hz), 2.89(2H, t, J = 7.8 Hz), 3.14-3.20 (1H, m), 3.35 (3H, s), 3.75 (2H, d, J =6.3 Hz), 6.82 (2H, dt, J = 9.3, 2.5 Hz), 7.11 (2H, d, J = 8.6 Hz). 115¹H-NMR (DMSO-d₆) δ: 0.89 (3H, s), 0.95 (3H, s), 1.22-1.62 (10H, m),1.60-1.66 (4H, m), 1.97 (1H, brs), 2.45-2.51 (2H, m), 2.74 (2H, t, J =7.6 Hz), 3.68-3.75 (2H, m), 6.81 (2H, d, J = 8.6 Hz), 7.10 (2H, d, J =8.6 Hz), 12.06 (1H, s). 116 ¹H-NMR (DMSO-d₆) δ: 0.26-0.31 (4H, m),1.17-1.26 (2H, m), 1.36-1.38 (1H, m), 1.56-1.65 (6H, m), 1.76-1.83 (4H,m), 1.93-2.03 (1H, m), 2.55-2.59 (2H, m), 3.64-3.72 (2H, m), 3.90-3.94(1H, m), 6.83 (2H, dt, J = 9.4, 2.5 Hz), 7.23 (2H, dt, J = 9.4, 2.5 Hz),12.23 (1H, s). 117 ¹H-NMR (CDCl₃) δ: 1.78-1.90 (2H, m), 1.93-2.11 (6H,m), 2.36 (2H, t, J = 7.0 Hz), 2.66 (2H, t, J = 8.0 Hz), 2.92 (2H, t, J =8.0 Hz), 4.52 (2H, s), 5.85 (1H, s), 6.86 (2H, d, J = 9.0 Hz), 7.12 (2H,d, J = 9.0 Hz). 118 ¹H-NMR (DMSO-d₆) δ: 1.30-1.40 (2H, m), 1.61-1.66(2H, m), 1.71-1.91 (8H, m), 1.77 (3H, d, J = 2.4 Hz), 2.26-2.38 (1H, m),2.56 (1H, dd, J = 15.1, 7.2 Hz), 2.60 (1H, dd, J = 15.1, 8.0 Hz), 3.78(2H, d, J = 6.8 Hz), 3.93 (1H, ddq, J = 8.0, 7.2, 2.4 Hz), 6.83-6.86(2H, m), 7.22-7.26 (2H, m), 12.26 (1H, br s). 119 ¹H-NMR (DMSO-d₆) δ:1.15-1.40 (14H, m), 1.45-1.52 (2H, m), 1.60-1.68 (1H, m), 1.71 (3H, d, J= 2.6 Hz), 1.79 (2H, brs), 1.95 (2H, brs), 2.21 (1H, dd, J = 14.7, 7.4Hz), 2.31 (1H, dd, J = 14.7, 7.4 Hz) 2.71 (2H, t, J = 7.4 Hz), 3.24 (1H,t, J = 6.2 Hz), 3.85-3.93 (2H, m), 4.30 (2H, s), 5.67 (1H, s), 6.78 (2H,d, J = 8.8 Hz), 7.18 (2H, d, J = 8.8 Hz). 120 ¹H-NMR (DMSO-d₆) δ: 0.98(3H, t, J = 7.1 Hz), 1.24-1.68 (21H, m), 1.93 (2H, t, J = 5.8 Hz), 2.14(1H, dd, J = 14.6, 5.8 Hz), 2.38 (1H, dd, J = 14.6, 7.9 Hz), 2.71 (2H,t, J = 7.4 Hz), 3.18 (3H, m), 4.30 (2H, s), 4.56 (1H, dd, J = 7.9, 5.8Hz), 5.62 (1H, s), 6.83 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 8.6 Hz).

Preparation examples of the present invention are as follows, but thepresent invention is not limited thereto.

Preparation Example 1 Capsule Preparation

1) Compound of Example 1 30 mg 2) Microcrystalline cellulose 10 mg 3)Lactose 19 mg 4) Magnesium stearate  1 mg

The ingredients 1) to 4) are mixed and filled into a gelatin capsule.

Preparation example 2 Tablet Preparation

1) Compound of Example 1 10 g 2) Lactose 50 g 3) Cornstarch 15 g 4)Carmellose calcium 44 g 5) Magnesium stearate  1 g

The whole amounts of 1), 2) and 3), and 30 g of 4) are kneaded withwater, dried in vacuo and sieved to give a granular powder 14 g of 4)and 1 g of 5) are mixed with the granular powder and the mixture iscompressed by a tableting machine. In this way, 1,000 tablets containing10 mg of the compound of Example 1 per tablet are prepared.

Test Example 1 Evaluation of Effect of Test Compounds on Ca²⁺Mobilization by Using a Stable GPR40-Expressing Cell Test Method (1)Cell

A stable human GPR40-expressing HEK293 cell was used.

(2) Cell Medium Preparation and Cell Culture

A cell suspension was prepared such that the above-mentioned cells werepresent at 6×10⁵ cells/mL in a cell culture medium (D-MEM (Nikken BioMedical Laboratory) supplemented with 10%(v/v) fetal bovine serum(Biowest) and 1%(v/v) penicillin-streptomycin solution (Invitrogen)).The cell suspension was plated in a 384-well plate (poly-D-lysine coatedplate; Falcon) in a volume of 25 μl/well, and the plate was incubated at37° C. in an atmosphere of 5% CO₂ overnight. Each test compound wasadded to the cell at each concentration as below, and then the change inintracellular calcium level was measured by FLIPR^(TETRA) (MolecularDevices). Before the FLIPR assay, the following preparative solutionswere prepared.

(3) Preparation of Preparative Solutions for FLIPR Assay

First, an assay buffer was prepared for use in the preparation of afluorescent dye solution and a diluent buffer solution. The assay bufferwas prepared by adding 1M HEPES solution (Invitrogen) to Hanks' BalancedSalt Solution (Invitrogen), followed by adjusting the pH to 7.4 with 1MNaOH (Nacalai Tesque). Next, the fluorescent dye solution and thediluent buffer solution were prepared. The fluorescent dye solution wasprepared in accordance with the instruction manual attached to Fluo-4NWcalcium assay kit (Invitrogen), followed by addition of bovine serumalbumin (Sigma) to a final concentration of 0.1%(w/v). The diluentbuffer solution was prepared by adding bovine serum albumin (Sigma) tothe assay buffer to give a final concentration of 0.1%(w/v).

(4) Pretreatment for FLIPR Assay

After removing a medium supernatant from the cell culture plateincubated overnight, the fluorescent dye solution was added to the platein a volume of 25 μl/well. The plate was incubated at 37° C. in anatmosphere of 5% CO₂ for 90 minutes to promote the fluorescent dyeuptake in the cell. Meanwhile, the test compounds (i.e., the compoundsprepared in Examples) dissolved in dimethyl sulfoxide (DMSO; NacalaiTesque) were diluted with the diluent buffer solution, to prepare eachcompound solution at each concentration. In addition, a palmitic acidsolution was prepared as a positive control solution (hereinafterabbreviated as PosiC). A 40 μl aliquot of each sample solution preparedas above was added to each well of a 384-well polypropylene plate toprepare a compound plate. Finally, after the sufficient uptake of thefluorescent dye in the cell, the cell plate and the compound plate wereset to FLIPR^(TETRA).

(5) FLIPR Assay

After the above pretreatment, the change in intracellular calcium levelwas measured by FLIPR^(TETRA) upon addition of 25 μl of each testcompound solution at each concentration.

The GPR40 agonist activity of each test compound at each concentrationwas determined as a relative activity level (% PosiC) with theintracellular calcium level induced by 80 μM palmitic acid (a GPR40agonist) set to 100%. Next, each compound concentration corresponding to50% PosiC was calculated based on the % PosiC value, to compare betweenagonist activities of the test compounds.

(6) Result

The results are shown in tables 39 to 42. In the tables, “++++”indicates 0.01 μM or more but less than 0.1 μM, “+++” indicates 0.1 μMor more but less than 1 μM, “++” indicates 1 μM or more but less than 10μM, and “+” indicates 10 μM or more for 50% posiC value.

In the tables, “N.T.” indicates “not tested”.

TABLE 39 Ex. No. 50% PosiC value 1 ++++ 2 ++++ 3 N.T. 4 ++++ 5 N.T. 6+++ 7 N.T. 8 +++ 9 +++ 10 N.T. 11 +++ 12 N.T. 13 N.T. 14 +++ 15 N.T. 16+++ 17 +++ 18 N.T. 19 ++++ 20 N.T. 21 + 22 +++ 23 N.T. 24 +++ 25 +++ 26N.T. 27 +++ 28 ++++ 29 +++ 30 +++

TABLE 40 Ex. No. 50% PosiC value 31 N.T. 32 +++ 33 N.T. 34 +++ 35 N.T.36 N.T. 37 +++ 38 N.T. 39 +++ 40 ++++ 41 ++++ 42 ++++ 43 N.T. 44 ++ 45N.T. 46 ++ 47 +++ 48 ++ 49 ++ 50 +++ 51 ++ 52 ++ 53 ++ 54 ++ 55 +++ 56++ 57 ++ 58 ++ 59 +++ 60 ++

TABLE 41 Ex. No. 50% PosiC value 61 + 62 + 63 +++ 64 +++ 65 ++ 66 +++67 + 68 ++ 69 ++ 70 +++ 71 ++ 72 ++ 73 +++ 74 N.T. 75 +++ 76 N.T. 77 +++78 ++ 79 N.T. 80 ++ 81 +++ 82 ++ 83 +++ 84 ++ 85 ++ 86 ++ 87 ++ 88 ++ 89++ 90 N.T.

TABLE 42 Ex. No. 50% PosiC value 91 +++ 92 +++ 93 N.T. 94 ++ 95 N.T. 96N.T. 97 +++ 98 N.T. 99 ++ 100 N.T. 101 +++ 102 N.T. 103 +++ 104 N.T. 105++ 106 N.T. 107 +++ 108 ++ 109 ++ 110 +++ 111 + 112 + 113 ++ 114 + 115++ 116 ++ 117 ++ 118 +++ 119 +++ 120 +++

Test Example 2 Evaluation of Test Compounds on Insulin Secretion UsingRat Isolated Islets of Langerhans Test Method

(1) Rat Islets of Langerhans are Isolated from Male Wister Rats (CharlesRiver Laboratories).

(2) Preparation of Each Solution for Use in the Isolation of Islets ofLangerhans

Each solution for use in the isolation of islets of Langerhans isprepared. A collagenase solution is prepared by dissolving collagenaseat a concentration of 1 mg/mL in Hanks' Balanced Salt Solution(Invitrogen) containing 1% (v/v) kanamycin sulfate (Invitrogen)(hereinafter referred to as HBSS/1%(v/v) kanamycin solution).Ficoll-Conray solution A is prepared by dissolving Ficoll (NacalaiTesque) in Milli Q water, followed by adding Conray400 (Conray is thetrademark registered by Daiichi Pharmaceutical Co.) thereto.

Ficoll-Conray solution D is prepared by mixing equal volumes of theabove solution A and Otsuka Distilled Water (Otsuka PharmaceuticalFactory). Ficoll-Conray solution C is prepared by mixing equal volumesof the Ficoll-Conray solutions A and D, and Ficoll-Conray solution B isprepared by mixing equal volumes of the Ficoll-Conray solutions A and C.A culture medium for islets of Langerhans is prepared by supplementingD-MEM (low glucose) (Nikken Bio Medical Laboratory) with 10%(v/v) fetalbovine serum (Biowest) and 1%(v/v) kanamycin sulfate (Invitrogen)(hereinafter referred to as D-MEM (LG)/10% FBS/1% kanamycin).

(3) Method for Isolating Islets of Langerhans from Wister Rats

Rats are anesthetized with pentobarbital and subjected to laparotomy forexposing the abdominal organs. After the common bile duct is clamped atthe duodenal side and then cannulated from the liver side, a collagenasesolution (1 mg/ml) is injected slowly to fill the pancreas with. Thepancreas is isolated and then incubated at 37° C. in an atmosphere of 5%CO₂ for about 20 minutes. The digested pancreas is suspended inHBSS/1%(v/v) kanamycin solution and the suspension is transferred to aglass tube. After centrifuging the suspension and then removing thesupernatant, the resulting precipitate is suspended in 3.8 mL ofFicoll-Conray solution A. On this, 1.8 mL of Ficoll-Conray solution B,1.8 mL of Ficoll-Conray solution C and 2.0 mL of Ficoll-Conray solutionD are superposed successively. After centrifugation, islets ofLangerhans present in the boundary between the solutions C and D arecollected into 6 mL of D-MEM (LG)/10% FBS/1% kanamycin, followed byfurther centrifugation. After removing the supernatant, the precipitateis resuspended in 6 mL of D-MEM (LG)/10% FBS/1% kanamycin. Afterremoving contaminants, the suspension is maintained at 37° C. in anatmosphere of 5% CO₂ until it is used for the evaluation of thecompounds.

(4) Method for Evaluating the Test Compounds on Insulin Secretion

D-MEM (LG)/10% FBS/1% kanamycin is added to a 6-well plate (Falcon) in avolume of 1.5 mL/well. After islets of Langerhans of almost the samesize are selected with a stereomicroscope, 5 islets are placed into eachwell. The islets of Langerhans are transferred into another 6-well plate(Falcon) filled with 3.3 mM glucose-contained Krebs RingerBicarbonate/0.2%(w/v) bovine serum albumin without free fatty acids(Sigma) (hereinafter referred to as KRB/0.2% BSA solution), andincubated at 37° C. in an atmosphere of 5% CO₂. After 60 minutes, theabove KRB/0.2% BSA solution is replaced with 3.3 mM or 11.2 mMglucose-contained KRB/0.2% BSA solution containing the respective testcompounds, followed by incubation at 37° C. in an atmosphere of 5% CO₂for 60 minutes. The respective test compounds are dissolved in dimethylsulfoxide (DMSO; Nacalai Tesque) and the final concentration of DMSO is1%(v/v) upon addition of the test compound to the cell. 60 minutes afteraddition of the respective test compounds, the supernatants arecollected. The insulin level in the supernatant is determined by usingultrasensitive rat insulin kit (Morinaga Institute of BiologicalScience). The result of the evaluation is shown as a relative activitylevel (% Control), which is represented as the insulin secretion levelof the group treated by the respective test compounds relative to thatof the control group.

Test Example 3 Glucose Tolerance Test in Wister Rats

Male Wister rats (Charles River Laboratories) are fasted for about 16hours since the day before the experiment day. 30 minutes after oraladministration of the respective test compounds at a dose of 0.1 to 30mg/kg body weight, rats are administered orally with a glucose solutionat a dose of 2 g/kg body weight. 0, 30, 60 and 120 minutes after theadministration, blood samples (about 200 μl) are collected via the tailvein of each rat to determine plasma glucose levels and plasma insulinlevels. The plasma glucose levels are determined by Hexokinase methodusing a biochemistry automatic analyzer. The plasma insulin levels aredetermined by ELISA using ultrasensitive rat insulin kit (MorinagaInstitute of Biological Science). The respective test compounds aresuspended in 0.5%(w/v) methyl cellulose for use in the oraladministration. The control group is administered with 0.5%(w/v) methylcellulose solution. For evaluation, a paired or multiple comparison testis performed with the control group to determine an efficacy.

INDUSTRIAL APPLICABILITY

The compound, a pharmaceutically acceptable salt thereof or a solvatethereof of the present invention is useful as a GPR40 agonist medicamentfor treating or preventing diabetes mellitus, hyperglycemia, impairedglucose tolerance, impaired fasting glucose and the like.

1.-21. (canceled)
 22. A process for preparing a spiro compound ofFormula [I]:

wherein: R¹ is a C₁-C₆alkyl group, a C2-C6alkenyl group, a C2-C6alkynylgroup, a phenyl group, a hydroxy group, or a five-membered heteroarylgroup which has at least one heteroatom selected from a nitrogen atom,an oxygen atom and a sulfur atom, and which is optionally substituted bya C₁-C₆alkyl group, or a di(C₁-C₆alkoxy)methyl group); m1 is 0, 1 or 2;m2 is 0 or 1; the spiro-ring AB is optionally substituted by 1 to 5 sameor different substituent(s) selected from the group consisting of: (1) ahydroxy group, (2) a C₁-C₆ alkyl group, (3) a C₁-C₆ alkoxy group and (4)an oxo group; n1 is 0, 1, 2, 3 or 4; n2 is 1, 2, 3 or 4; n3 is 0, 1 or 2with the proviso that n2+n3 is 2, 3 or 4; and a bond represented by thesymbol:

means a single bond or a double bond with the proviso that threecontiguous carbon atoms do not constitute an allene bond represented bythe formula:C═C═C; wherein the process comprises hydrolyzing an intermediateaccording to Compound (3):

wherein R⁵¹ is a C₁-C₆alkyl group and R^(1′) corresponds to R¹.
 23. Theprocess of claim 22 wherein the hydrolyzing is carried out in a solventin the presence of a base.
 24. The process of claim 23 wherein thesolvent comprises an ether solvent, an alcoholic solvent, or a mixturethereof.
 25. The process of claim 23 wherein the base comprises anaqueous solution of sodium hydroxide or potassium hydroxide.
 26. Theprocess of claim 22 wherein the compound according to Compound (3) isprepared by the process of condensing a spiro intermediate according toCompound (1):

with an intermediate according to Compound (2):

wherein X⁵¹ and X⁵² are the same or different and each represents ahydroxy group or a leaving group.
 27. The process of claim 26 whereinX⁵² is a leaving group and X⁵¹ is a hydroxy group.
 28. The process ofclaim 26 wherein the leaving group is a chlorine atom, a bromine atom,an iodine atom, or a methanesulfonyloxy group.
 29. The process of claim26 wherein the condensing is carried out in the presence of a condensingreagent.
 30. The process of claim 29 wherein the condensing reagentcomprises 1,1′-(azodicarbonyl)dipiperidine or triphenylphosphine. 31.The process of claim 26 wherein the condensing is carried out in thepresence of a solvent.
 32. The process of claim 31 wherein the solventcomprises an ether solvent.
 33. The process of claim 31 wherein thesolvent comprises a polar solvent.
 34. The process of claim 26 whereinthe condensing is carried out in the presence of a base.
 35. The processof claim 34 wherein the base comprises an alkali metal carbonate. 36.The process of claim 35 wherein the alkali metal carbonate is potassiumcarbonate or cesium carbonate.
 37. A process for preparing anintermediate according to Compound (1b):

wherein: the spiro-ring AB is optionally substituted by 1 to 5 same ordifferent substituent(s) selected from the group consisting of: (1) ahydroxy group, (2) a C₁-C₆ alkyl group, (3) a C₁-C₆ alkoxy group and (4)an oxo group; L_(v1) is a leaving group; m1 is 0, 1 or 2; n1 is 0, 1, 2,3 or 4; n2 is 1, 2, 3 or 4; n3 is 0, 1 or 2 with the proviso that n2+n3is 2, 3 or 4; and a bond represented by the symbol:

means a single bond or a double bond with the proviso that threecontiguous carbon atoms do not constitute an allene bond represented bythe formula:C═C═C; comprising reacting an intermediate according to Compound (1a):

with a halogenating agent in a solvent in the presence of an additive atroom temperature or with heat.
 38. The process of claim 37 wherein thehalogenating reagent comprises N-bromosuccinimide.
 39. The process ofclaim 37 wherein the additive comprises triphenylphosphine.
 40. Theprocess of claim 37 wherein the solvent comprises a halogenatedhydrocarbon solvent.
 41. The process of claim 37 wherein the solventcomprises chloroform.
 42. A process for preparing an intermediateaccording to Compound (1a-1a):

wherein: the spiro-ring AB is optionally substituted by 1 to 5 same ordifferent substituent(s) selected from the group consisting of: (1) ahydroxy group, (2) a C₁-C₆ alkyl group, (3) a C₁-C₆ alkoxy group and (4)an oxo group; n1 is 0, 1, 2, 3 or 4; n2 is 1, 2, 3 or 4; and a bondrepresented by the symbol:

means a single bond or a double bond with the proviso that threecontiguous carbon atoms do not constitute an allene bond represented bythe formula:C═C═C; comprising: (a) reacting an intermediate according to Compound(5-1):

with di(C₁-C₆alkyl) carbonate in a solvent in the presence of a base atroom temperature or with heat to form an intermediate according toCompound (5-1a):

wherein R⁵¹ is C₁-C₆ alkyl; (b) reacting the intermediate according toCompound (5-1a) with a reducing agent in a solvent at room temperatureor with heat, or by catalytic reduction with a catalyst in an atmosphereof hydrogen to form an intermediate according to Compound (5-1b):

(c) reacting the intermediate according to Compound (5-1b) withmethanesulfonyl chloride in a solvent under basic conditions at roomtemperature or with heat to form an intermediate according to Compound(5-1c):

wherein L_(v2) is a leaving group; (d) reacting the intermediateaccording to Compound (5-1c) with a base in a solvent at roomtemperature or with heat to form an intermediate according to Compound(5-1d):

wherein R¹⁰⁰ is C₁-C₆ alkyl; and (e) reacting the intermediate accordingto Compound (5-1d) with a reducing agent in a solvent with cooling or atroom temperature to form the intermediate of Compound (1a-1a).
 43. Theprocess of claim 42 wherein the di(C₁-C₆alkyl)carbonate of step (a) isdimethyl carbonate.
 44. The process of claim 42 wherein the base of step(a) is sodium hydride or potassium tert-butoxide.
 45. The process ofclaim 42 wherein the solvent of step (a) comprises an ether solvent. 46.The process of claim 45 wherein the ether solvent of step (a) comprisestetrahydrofuran.
 47. The process of claim 42 wherein the reducing agentof step (b) comprises sodium borohydride.
 48. The process of claim 42wherein the solvent of step (b) comprises an ether solvent or analcoholic solvent or a mixture thereof.
 49. The process of claim 48wherein the solvent of step (b) comprises tetrahydrofuran or methanol ora mixture thereof.
 50. The process of claim 42 wherein the catalyst ofstep (b) comprises platinum oxide.
 51. The process of claim 42 whereinthe base of step (c) is an organic base.
 52. The process of claim 51wherein the organic base of step (c) is triethylamine or pyridine. 53.The process of claim 42 wherein the solvent of step (c) comprises ahalogenated hydrocarbon.
 54. The process of claim 53 wherein thehalogenated hydrocarbon of step (c) is chloroform.
 55. The process ofclaim 42 wherein the reacting of step (c) is carried out in the presenceof an additive.
 56. The process of claim 55 wherein the additive of step(c) comprises 4-dimethylaminopyridine.
 57. The process of claim 42wherein the base of step (d) is an organic base.
 58. The process ofclaim 57 wherein the organic base of step (d) is1,8-diazabicyclo[5.4.0]undec-7-ene.
 59. The process of claim 42 whereinthe solvent of step (d) comprises an ether solvent.
 60. The process ofclaim 59 wherein the ether solvent of step (d) is tetrahydrofuran. 61.The process of claim 42 wherein the reducing agent of step (e) comprisesdiisobutylaluminum hydride.
 62. The process of claim 42 wherein thesolvent of step (e) comprises an ether solvent.
 63. The process of claim62 wherein the ether solvent of step (e) is tetrahydrofuran.
 64. Aprocess for preparing an intermediate according to Compound (4):

wherein: m1 is 0, 1 or 2; m2 is 0 or 1; the spiro-ring AB is optionallysubstituted by 1 to 5 same or different substituent(s) selected from thegroup consisting of: (1) a hydroxy group, (2) a C₁-C₆ alkyl group, (3) aC₁-C₆ alkoxy group and (4) an oxo group; n1 is 0, 1, 2, 3 or 4; n2 is 1,2, 3 or 4; and a bond represented by the symbol:

means a single bond or a double bond with the proviso that threecontiguous carbon atoms do not constitute an allene bond represented bythe formula:C═C═C; comprising condensing an intermediate according to Compound (1):

wherein X⁵¹ is a hydroxy group or a leaving group; with an intermediateaccording to Compound (20):

wherein X⁵² is a hydroxy group or a leaving group.
 65. The process ofclaim 64 wherein the condensing is carried out in the presence of acondensing reagent.
 66. The process of claim 65 wherein the condensingreagent comprises 1,1′-(azodicarbonyl)dipiperidine ortriphenylphosphine.
 67. The process of claim 64 wherein the condensingis carried out in the presence of a solvent.
 68. The process of claim 67wherein the solvent comprises an ether solvent.
 69. The process of claim67 wherein the solvent comprises a polar solvent.
 70. The process ofclaim 64 wherein the condensing is carried out in the presence of abase.
 71. The process of claim 70 wherein the base comprises an alkalimetal carbonate.
 72. The process of claim 71 wherein the alkali metalcarbonate is potassium carbonate or cesium carbonate.
 73. Anintermediate compound selected from:

wherein: R^(1′) is a C₁-C₆alkyl group, a C2-C6alkenyl group, aC2-C6alkynyl group, a phenyl group, a hydroxy group, a five-memberedheteroaryl group which has at least one heteroatom selected from anitrogen atom, an oxygen atom and a sulfur atom, and which may besubstituted by a C1-C6alkyl group, or a di(C₁-C₆alkoxy)methyl group);R⁵¹ is a C₁-C₆alkyl group; R¹⁰⁰ is a C₁-C₆alkyl group; L_(v1) is aleaving group; L_(v2) is a leaving group; X⁵¹ and X⁵² are the same ordifferent and each represents a hydroxy group or a leaving group; m1 is0, 1 or 2; m2 is 0 or 1; the spiro-ring AB is optionally substituted by1 to 5 same or different substituent(s) selected from the groupconsisting of: (1) a hydroxy group, (2) a C₁-C₆ alkyl group, (3) a C₁-C₆alkoxy group and (4) an oxo group; n1 is 0, 1, 2, 3 or 4; n2 is 1, 2, 3or 4; n3 is 0, 1 or 2 with the proviso that n2+n3 is 2, 3 or 4; and abond represented by the symbol:

means a single bond or a double bond with the proviso that threecontiguous carbon atoms do not constitute an allene bond represented bythe formula:C═C═C.